CN112409538A

CN112409538A - Molecularly imprinted polymer capable of being combined with acetate, preparation method thereof, pharmaceutical composition containing molecularly imprinted polymer and pharmaceutical application of molecularly imprinted polymer

Info

Publication number: CN112409538A
Application number: CN202011295816.3A
Authority: CN
Inventors: 高志钊; 李伟业; 潘松升; 黎嘉麟
Original assignee: Clive Life Sciences Ltd
Current assignee: Li Baolai Science Co ltd
Priority date: 2019-11-29
Filing date: 2020-11-18
Publication date: 2021-02-26
Anticipated expiration: 2040-11-18
Also published as: CN112409538B

Abstract

The invention provides a molecularly imprinted polymer capable of binding acetate and other target molecules, a preparation method thereof, a pharmaceutical composition containing the molecularly imprinted polymer and application thereof in preparing a medicament for treating a disease related to accumulation of acetate and other target molecules.

Description

Molecularly imprinted polymer capable of being combined with acetate, preparation method thereof, pharmaceutical composition containing molecularly imprinted polymer and pharmaceutical application of molecularly imprinted polymer

Background

The human gastrointestinal tract contains trillions of microorganisms that form a complex community that interacts intimately with human cells. This intestinal microbial substance, also known as the microbiota, is metabolically active and produces a variety of metabolites. Intestinal microbial metabolites include short chain fatty acids such as acetate, vitamins, bile acids, coenzymes, amino acid derivatives and other organic molecules. These metabolites regulate the functional role of the gut microbiota and influence the physiological processes of the microorganism and the host. These physiological processes are often associated with the development of disease. Thus, the intestinal microbiota composition and its metabolites play an important role in the development of diseases, including digestive and systemic diseases (Tang et al, 2017, Circ Res.120(7): 1183-1196). For example, acetate production by the gut microbiota is associated with metabolic syndrome and obesity (Perry et al, 2016, Nature 534: 213-217).

A molecularly imprinted polymer is a polymer whose pores in the polymer matrix have the ability to complement and affinity with the template molecule. Molecularly imprinted polymers are typically formed by polymerizing functional monomers in the presence of a template molecule that is subsequently extracted leaving complementary voids (U.S. Pat. Nos. 6,638,498,8,287,908 and 9,149,737). Although molecularly imprinted polymers have been described in the art for binding various template molecules, molecularly imprinted polymers have not been widely used for treating human diseases.

Therefore, there is an urgent need for new molecularly imprinted polymers for the treatment of various diseases.

Disclosure of Invention

The invention provides a molecularly imprinted polymer capable of being combined with acetate, which is characterized by comprising one or more functional molecules, wherein the functional molecules comprise N, N '-methylene-bis (acrylamide) and ethylene glycol dimethacrylate, and the molar ratio of the N, N' -methylene-bis (acrylamide) to the ethylene glycol dimethacrylate is 1: 1-4: 5.

In one embodiment of the present invention, a molecularly imprinted polymer is provided, wherein the molecularly imprinted polymer is capable of binding acetate in the human gastrointestinal tract.

In an embodiment of the present invention, a molecularly imprinted polymer is provided, wherein at least 90 mol% of functional molecules in the molecularly imprinted polymer are functional cross-linking agents.

In an embodiment of the present invention, a molecularly imprinted polymer is provided, wherein at least 95% mol of functional molecules in the molecularly imprinted polymer are functional cross-linking agents.

In an embodiment of the present invention, a molecularly imprinted polymer is provided, wherein at least 97 mol% of functional molecules in the molecularly imprinted polymer are functional cross-linking agents.

In one embodiment of the present invention, a molecularly imprinted polymer is provided, wherein at least 99 mol% of functional molecules in the molecularly imprinted polymer are functional cross-linking agents.

In an embodiment of the present invention, a molecularly imprinted polymer is provided, wherein the molecularly imprinted polymer has an acetate binding capacity in water from 20g to 40g per g of acetate bound to the molecularly imprinted polymer.

In one embodiment of the present invention, a molecularly imprinted polymer is provided, wherein the molecularly imprinted polymer has a greater affinity for acetate than chloride.

In an embodiment of the present invention, there is provided a molecularly imprinted polymer, wherein the molecularly imprinted polymer has a D (v,0.5) particle size of 10 μm to 50 μm.

In an embodiment of the present invention, there is provided a molecularly imprinted polymer, wherein the molecularly imprinted polymer has a D (v,0.5) particle size of 10 μm to 40 μm.

In an embodiment of the present invention, there is provided a molecularly imprinted polymer, wherein the molecularly imprinted polymer has a D (v,0.5) particle size of 15 μm to 25 μm.

In an embodiment of the present invention, a molecularly imprinted polymer is provided, wherein the molar ratio of N, N' -methylenebis (acrylamide) to ethylene glycol dimethacrylate is 1:1.

In one embodiment of the present invention, there is provided a molecularly imprinted polymer, wherein the molecularly imprinted polymer comprises polymerizing and crosslinking with the N, N' -methylenebis (acrylamide) and the ethylene glycol dimethacrylate in the presence of one or more template molecules comprising acetate and/or a salt thereof.

In one embodiment of the present invention, there is provided a molecularly imprinted polymer, wherein the one or more template molecules comprise potassium acetate.

In another aspect, the invention provides a pharmaceutical composition comprising the molecularly imprinted polymer and pharmaceutically acceptable excipients thereof.

In another aspect, the invention provides the use of the molecularly imprinted polymer for the preparation of a pharmaceutical composition for the treatment of a subject diagnosed with or at risk of a condition associated with acetate accumulation.

In another aspect, the present invention provides a method for preparing a pharmaceutical composition comprising a molecularly imprinted polymer capable of binding acetate, the method comprising polymerizing and crosslinking N, N '-methylenebis (acrylamide) and ethylene glycol dimethacrylate in the presence of one or more template molecules, wherein the molar ratio of N, N' -methylenebis (acrylamide) to ethylene glycol dimethacrylate is from 1:1 to 4:5, wherein the one or more template molecules comprise acetate and/or a salt thereof.

In one embodiment of the present invention, a method of preparing a pharmaceutical composition is provided, wherein the one or more template molecules comprise acetate.

In one embodiment of the present invention, a method for preparing a pharmaceutical composition is provided, wherein the acetate salt comprises potassium acetate and/or sodium acetate.

In one embodiment of the present invention, a method for preparing a pharmaceutical composition is provided, wherein the acetate salt is potassium acetate.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a molecularly imprinted polymer capable of binding acetate and a pharmaceutically acceptable excipient thereof, wherein the molecularly imprinted polymer comprises one or more functional molecules comprising N, N '-methylenebis (acrylamide) and ethylene glycol dimethacrylate, and wherein the molar ratio of the N, N' -methylenebis (acrylamide) to the ethylene glycol dimethacrylate is 1:1 to 4: 5.

In one embodiment of the present invention, a pharmaceutical composition is provided, wherein the molecularly imprinted polymer is capable of binding acetate in the human gastrointestinal tract.

In one embodiment of the present invention, a pharmaceutical composition is provided, wherein at least 80% mol of the functional molecules in the molecularly imprinted polymer are functional cross-linking agents.

In an embodiment of the present invention, a pharmaceutical composition is provided, wherein the molecularly imprinted polymer has an acetate binding capacity in water ranging from 5g to 40g acetate per g molecularly imprinted polymer.

In an embodiment of the present invention, a pharmaceutical composition is provided, wherein the molecularly imprinted polymer has an acetate binding capacity in water ranging from 20g acetate to 40g acetate per g molecularly imprinted polymer.

In one embodiment of the present invention, a pharmaceutical composition is provided, wherein the molecularly imprinted polymer has a greater affinity for acetate than chloride.

In one embodiment of the present invention, there is provided a pharmaceutical composition, wherein the molecularly imprinted polymer has a particle size D (v,0.5) of 10 μm to 50 μm.

In one embodiment of the present invention, there is provided a pharmaceutical composition, wherein the molecularly imprinted polymer has a particle size D (v,0.5) of 10 μm to 40 μm.

In one embodiment of the present invention, there is provided a pharmaceutical composition, wherein the molecularly imprinted polymer has a particle size D (v,0.5) of 15 μm to 25 μm.

In one embodiment of the present invention, a pharmaceutical composition is provided, wherein the molar ratio of N, N' -methylenebis (acrylamide) to ethylene glycol dimethacrylate is 1:1.

In another aspect, the invention provides the use of a pharmaceutical composition in the manufacture of a medicament for treating acetate in the gastrointestinal tract of a sequestered subject.

In another aspect, the invention provides the use of a pharmaceutical composition in the manufacture of a medicament for the treatment of weight loss in a subject.

In another aspect, the invention provides the use of a pharmaceutical composition in the manufacture of a medicament for the treatment of conditions associated with acetate accumulation, including metabolic syndrome.

In another aspect, the invention provides the use of a pharmaceutical composition in the manufacture of a medicament for the treatment of conditions associated with acetate accumulation, including obesity.

Drawings

FIG. 1 is a schematic diagram showing the synthesis of a molecularly imprinted polymer.

FIG. 2 is a schematic showing the synthesis of an exemplary acetate binding molecularly imprinted polymer.

Fig. 3 is an exemplary illustration showing the binding and sequestration of an acetate binding molecularly imprinted polymer to an acetate target molecule.

FIG. 4 is a schematic diagram showing the study timeline described in example 1.

Figures 5A-5F show data relating to the safety and efficacy of acetate-binding molecularly imprinted polymers in vivo studies, as described in example 1. FIG. 5A: randomly grouping the average body weights of the three groups of mice before and after; FIG. 5B: body weight change at study end randomized by group; FIG. 5C: total cholesterol; FIG. 5D: liver enzyme ALT levels; FIG. 5E: inflammatory gene expression level; FIG. 5F: creatinine levels.

Fig. 6 shows the structures of the functional monomer, the functional crosslinker, the second crosslinker, the template molecule and the initiator used to make the molecularly imprinted polymer of example 2.

FIGS. 7A-7B show the synthesis scheme of acetate binding molecularly imprinted polymer P1-P9. FIG. 7A, P1-P5, P8; FIG. 7B, P6-P7, P9.

FIGS. 8A-8C show thermographic images of acetate binding molecularly imprinted polymers P6 (FIG. 8A), P8 (FIG. 8B) and P9L (FIG. 8C).

FIG. 9 shows that in the study of example 2, acetate-binding molecularly imprinted polymer P9 was administered_LThe weight of the mouse (c).

FIG. 10 shows that in the study of example 2, P9 was administered_LGlucose levels, liver enzymes (ALT, AST), lipids (cholesterol), markers of mucosal damage (iFABP, FIT) in mice.

Fig. 11 shows the average body weight of mice administered with acetate-binding molecularly imprinted polymer P8.

Detailed Description

1. Definition of

As used herein, the following terms have the following meanings:

functional crosslinking agent:the term "functional crosslinker" as used herein refers to a functional molecule capable of crosslinking two or more polymer chains. The functional crosslinker may also extend the polymer chain during the polymerization reaction. Exemplary functional crosslinkers are described in section 2.1.1.

Functional molecule:the term "functional molecule" as used herein refers to a molecule having one or more groups capable of binding to or interacting with a target molecule through non-covalent interactions (e.g., through hydrogen bonds, ionic bonds, pi-pi interactions, cation-pi interactions, anion-pi interactions, van der Waals interactions, or hydrophobic interactions). Exemplary functional groups include amine, amide, carboxyl, hydroxyl, and aromatic groups. The functional molecules include functional monomers and functional cross-linking agents. Exemplary functional molecules are described in section 2.1.

Functional monomer:the term "functional monomer" as used herein refers to a functional molecule that can extend a polymer chain but does not crosslink two or more polymer chains during polymerization. Exemplary functional monomers are described in section 2.1.2.

Initiator:the term "initiator" as used herein refers to a molecule capable of initiating a polymerization and/or crosslinking reaction. Initiators known in the art include thermal Initiators and photoinitiators (Myers, T.N.2002, "Initiators, Free-Radiica," Encyclopedia of Polymer Science and Technology; the contents of which are incorporated herein by reference). Exemplary functional monomers are described in section 2.3.

Molecularly imprinted polymer:the term "molecularly imprinted polymer" or simply "MIP" as used herein refers to a cross-linked polymer having empty pores that are complementary and compatible with a target molecule. The molecularly imprinted polymer may have an affinity for multiple target molecules (e.g., a molecularly imprinted polymer with affinity for acetate may have an affinity for one or more other short chain fatty acids). The molecularly imprinted polymers of the invention typically comprise one or more functional molecules. It is to be understood that in the expressions "molecularly imprinted polymer comprises one or more functional molecules", "molecularly imprinted polymer comprises one or more functional molecules and one or more second cross-linking agents" and the like refer to a molecularly imprinted polymer having incorporated therein one or more functional molecules and one or more second cross-linking agents (when present).

A second crosslinking agent:the term "second crosslinker" as used herein refers to a crosslinker other than a functional crosslinker. The molecularly imprinted polymer of the present invention may be prepared from one or more second crosslinking agents in combination with one or more functional crosslinking agents, or the molecularly imprinted polymer of the present invention may be prepared from one or more second crosslinking agents in combination without one or more functional crosslinking agents. Thus, for the avoidance of doubt, it is to be understood that the term "second crosslinker" does not imply that the second crosslinker is present with or used in combination with any other crosslinker, although in some embodiments one or more second crosslinkers are present with one or more second crosslinkersThe functional crosslinking agents are used in combination.

Target molecule:the term "target molecule" as used herein refers to a molecule (which may be an ion) that selectively binds to a molecularly imprinted polymer. The target molecule may be a template molecule or an ion of a template molecule used in the synthesis of the molecularly imprinted polymer. The target molecule may also be different from the template molecule used to synthesize the molecularly imprinted polymer. For example, the target molecule may be a molecule of similar size and/or charge to the template.

Template molecule: the term "template molecule" as used herein refers to a molecule (which may be an ion) that is used in a molecularly imprinted polymer during its synthesis. The term "template molecule" may refer to, for example, an acid, base, or salt used to prepare the polymer mixture, as well as the corresponding species (e.g., uncharged molecules or ions) that may be present in the polymer mixture. For example, a polymerization mixture made from potassium acetate may contain undissociated potassium acetate as well as dissociated acetate ions.

2. Molecularly Imprinted Polymers (MIPs)

The present invention provides molecularly imprinted polymers capable of binding a target molecule (e.g., acetate). The molecularly imprinted polymers of the present invention typically comprise one or more functional molecules (e.g., one or more functional crosslinkers and/or one or more functional monomers).

Accordingly, in various aspects, the present invention provides molecularly imprinted polymers comprising (1) one or more functional crosslinkers; (2) one or more functional monomers; or (3) one or more functional crosslinkers and one or more functional monomers. The molecularly imprinted polymer of the present invention may comprise additional components such as one or more second cross-linking agents and/or one or more monomers that are not functional monomers. In some embodiments, the functional molecule and any second crosslinker together comprise 80% or more (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) of the dry weight of the molecularly imprinted polymer, with the remainder, if any, being one or more additional components, such as monomers of non-functional monomers and/or residual template molecules. In some embodiments, the molecularly imprinted polymers of the present invention include one or more functional crosslinkers, one or more second crosslinkers, and no or only a small amount of functional monomers (e.g., less than 20 mol% or less, 15 mol% or less, 10 mol% or less, 5 mol% or less, 4 mol% or less, 3 mol% or less, 2 mol% or less, 1 mol% or less, or 0% of the functional molecules in the molecularly imprinted polymer are functional monomers). In some embodiments, the molecularly imprinted polymers of the present invention include one or more functional cross-linkers, one or more second cross-linkers, and no functional monomers.

Generally, molecularly imprinted polymers in the art are made from functional monomers. However, compared with the molecularly imprinted polymer prepared by the functional monomer, the molecularly imprinted polymer prepared by the functional cross-linking agent has unexpected superior properties, such as higher target molecule binding capacity. Without being bound by theory, molecularly imprinted polymers made with functional crosslinkers that do not contain functional monomers or contain only small amounts of functional monomers (e.g., where 20 mol% or less, 15 mol% or less, 10 mol% or less, 5 mol% or less, 4 mol% or less, 3 mol% or less, 2 mol% or less, 1 mol% or less, or 0% of the functional molecules are functional monomers) have higher rigidity and selectivity to target molecules than molecularly imprinted polymers made with large amounts of functional monomers. Also, without being bound by theory, increased robustness of the molecularly imprinted polymer and its target molecule binding site may result in greater selectivity.

Section 2.1.1 describes exemplary functional crosslinkers that can be used in the molecularly imprinted polymer of the invention. Section 2.1.2 describes exemplary functional monomers that can be used in the molecularly imprinted polymers of the invention. One or more second crosslinking agents may be used to crosslink the polymers in the molecularly imprinted polymer, either alone or in combination with one or more functional crosslinking agents. Section 2.2 describes exemplary second crosslinkers. Polymerization of the functional monomer and/or functional crosslinker may be initiated using one or more initiators known in the art, for example, one or more initiators described in section 2.3. Exemplary template molecules for making molecularly imprinted polymers of the invention, such as acetate-binding molecularly imprinted polymers, are described in section 2.4. An exemplary molecularly imprinted polymer synthesis process is described in section 2.5.

2.1. Functional molecules

Functional molecules include monomers and cross-linking agents having one or more groups capable of non-covalent bonding (e.g., through hydrogen bonding, ionic bonding, van der waals interactions, or hydrophobic bonding) with a target molecule. Exemplary functional groups include amine, amide, carboxyl, hydroxyl, and aromatic groups.

The molecularly imprinted polymer of the present invention may be made of a functional crosslinking agent, a functional monomer, or a combination of a functional crosslinking agent and a functional monomer. The molecularly imprinted polymers of the present invention may be composed of a single type of functional molecule (e.g., a single functional crosslinker or a single functional monomer) or a combination of functional molecules (e.g., a combination of two or more functional crosslinkers, a combination of two or more functional monomers, or a combination of one or more functional crosslinkers and one or more functional monomers).

The ratio of functional molecules to cross-linking agents (e.g., functional cross-linking agents and/or second cross-linking agents) can vary, for example, between 1:5 and 5:1 (e.g., 1:5 to 1:1 or 1:1 to 5: 1). For example, the ratio may be 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 2:5, 3:5, 4:5, 6:5, and may be any range defined by any two of the ratios described above. In some embodiments, the ratio is 1: 5. In other embodiments, the ratio is 2: 5. In other embodiments, the ratio is 3: 5. In other embodiments, the ratio is 4: 5. In other embodiments, the ratio is 6: 5. In other embodiments, the ratio is 1:1.

2.1.1. Functional crosslinking agent

Exemplary functional crosslinkers that can be used to prepare the molecularly imprinted polymers of the invention (e.g., acetate-binding molecularly imprinted polymers) include amide-containing crosslinkers (e.g., N' -methylenebis (acrylamide) (MBA)) and urea-containing crosslinkers (e.g., 1, 3-bis (4-vinylphenyl) urea and 1, 3-bis (4- (allyloxy) phenyl) urea, 1, 3-diallylurea). In some embodiments, the acetate binding molecularly imprinted polymers of the present invention comprise MBA.

One skilled in the art may select additional or alternative crosslinking agents having one or more groups capable of non-covalent bonding (e.g., through hydrogen bonding, ionic bonding, van der waals interactions, or hydrophobic bonding) with a given target molecule.

2.1.2. Functional monomer

Exemplary functional monomers that can be used to prepare the molecularly imprinted polymers of the present invention (e.g., acetate-binding molecularly imprinted polymers) include acrylamides, such as acrylamide (propan-2-amide), N-alkylacrylamides, and methacrylamide.

Examples of acrylamide include N-methacrylamide, N-ethylacrylamide, N-isopropylacrylamide, N-methylmethacrylate, N- (3-aminopropyl) methacrylamide, N- (2-oxyethyl) -2-acrylamide and N- (2-aminopyridine) methacrylamide.

Other exemplary functional monomers that may be used to prepare the molecularly imprinted polymer (e.g., an acetate-binding molecularly imprinted polymer) include N-vinylacetamide, N- [ [3- (vinylsulfonyl) -1-acetonyl ] amino ] methyl ] -2-acrylamide, 4-vinylbenzamide, N-alkyl- (4-vinylbenzamide), N' -diethyl (4-vinylphenyl) amide, hydroxy-substituted styrene, amide-substituted styrene, N- (diaminoethylene) -2-methylpropen-2-enamine, N-allylurea, and 1-allyl-2-thiourea.

One skilled in the art may select additional or alternative monomers having one or more groups capable of non-covalent bonding (e.g., through hydrogen bonding, ionic bonding, van der waals interactions, or hydrophobic bonding) with a given target molecule.

2.2. Second crosslinking agent

Exemplary second crosslinking agents that can be used to prepare the molecularly imprinted polymer include diallyl derivatives, divinyl derivatives, dimethacrylate derivatives, and bisacrylamide derivatives. Other types of crosslinking agents known in the art may also be used.

Exemplary classes of second crosslinkers that can be used to make the molecularly imprinted polymers of the invention (e.g., acetate-binding molecularly imprinted polymers) include Ethylene Glycol Dimethacrylate (EGDA), ethylene glycol diacrylate, 1, 2-diallyloxybenzene, divinylbenzene, 1, 3-diisopropenylbenzene, divinylsuccinic acid, 1, 3-divinyltetramethyldisiloxane, tri (ethylene glycol) divinyl ether, di (ethylene glycol) divinyl ether, trimethylolpropane trimethacrylate, pentaerythritol triacrylate, and combinations thereof. In some embodiments, the acetate binding molecularly imprinted polymers of the present invention comprise EGDA.

When the molecularly imprinted polymer is manufactured using the second crosslinking agent, the molar ratio of the functional molecule (e.g., the functional crosslinking agent and/or the functional molecule) to the second crosslinking agent may be, for example, 1:5 to 5:1 (e.g., 1:5 to 1:1 or 1:1 to 5: 1). For example, the ratio may be 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, or 5:1, and may be any range defined by any two of the ratios described above. In some embodiments, the ratio is 1:1 to 4: 5. In some embodiments, the ratio is 1:1.

2.3. Initiator

The initiator may be used to initiate polymerization of a mixture comprising one or more functional crosslinkers and/or one or more functional monomers. Polymerization initiators are known in the art and include thermal initiators and photoinitiators. Exemplary Initiators include potassium persulfate, sodium persulfate, ammonium persulfate, dimethyl azobisisobutyrate (V601), Azobisisobutyronitrile (AIBN), benzoyl peroxide, t-butyl hydroperoxide, acetyl peroxide, 2-hydroxy-4' - (2-hydroxyethoxy) -2 methylpropanol, benzene derivatives, and other Free Radical Initiators reported in Myers, T.N.2002, "Initiators, Free-Radiica," Encyclopedia of Polymer Science and technology.

2.4. Template molecule and target molecule

The template molecule used for the synthesis of the molecularly imprinted polymer may be the same as the desired target molecule, e.g. a metabolite derived from intestinal microbes or toxins. For example, the target molecule may be a short chain fatty acid (e.g., acetate), a bile acid, a vitamin, an enzyme cofactor, an amino acid (e.g., phenylalanine), an amino acid derivative, or a peptide, and the template molecule may be identical to the target molecule.

Alternatively, the template molecule may resemble the target molecule in size, shape, charge, or a combination of these. Thus, for example, acetate-binding molecularly imprinted polymers may be prepared using another short chain fatty acid as a template (e.g., propionic acid, butyric acid, or isobutyric acid). A non-limiting list of templates for preparing molecularly imprinted polymers that bind acetate includes acetate, propionate, isobutyrate, butyrate, pivalate, benzoate, malonate, succinate, bicarbonate, carbonate, and the like. Exemplary salts include potassium and sodium salts.

In some embodiments, the acetate binding molecularly imprinted polymers of the present invention (a) are imprinted using a template in which acetate is the only organic moiety and/or (b) are imprinted using a template having a molecular weight of no more than 200g/mol, no more than 175g/mol, no more than 150g/mol, no more than 125g/mol, or no more than 100 g/mol.

In some embodiments, the template comprises an acetate salt (e.g., potassium acetate or sodium acetate) and/or a compound (e.g., an organic compound) that does not have covalently bound acetate or acetate groups (referred to as "acetate-bound organic molecules" for convenience). In some embodiments, the acetic acid binding organic molecule is 2-methyl-4-chlorophenoxyacetic acid, 2, 4-dichlorophenoxyacetic acid, 2,4, 5-trichlorophenoxyacetic acid, cortisone acetate, dexamethasone acetate, hydrocortisone acetate, betamethasone acetate 21, or phenoxyacetic acid. In some embodiments, the template is an inorganic acetate, such as potassium acetate or sodium acetate.

2.5 exemplary molecularly imprinted Polymer Synthesis Process

The molecularly imprinted polymer of the present invention can be synthesized under conditions such that its particle size, stability and selectivity are at optimum levels, for example, suitable for oral administration. The following synthetic procedures for molecularly imprinted polymers are exemplary procedures for making molecularly imprinted polymers (e.g., acetate-binding molecularly imprinted polymers) of the present invention. Additional molecularly imprinted polymer synthesis procedures are described in the examples and specific examples. Exemplary molecularly imprinted polymer synthesis processes and the processes described in the examples and specific examples can be used to produce different molecularly imprinted polymers by replacing template molecules, functional cross-linkers, functional monomers, secondary cross-linkers, and the like.

Process for synthesizing molecularly imprinted polymer

A mixture (e.g., at 60 ℃ to 80 ℃) comprising one or more solvents (e.g., methanol), one or more template molecules (e.g., as described in section 2.4), and one of (i) to (iv) below, degassed by bubbling through an inert gas (e.g., argon or nitrogen) for a period of time (e.g., about 15 minutes).

(i) One or more functional monomers and one or more second crosslinkers (e.g., one or more functional monomers and/or one or more second crosslinkers described in sections 2.1 and 2.2);

(ii) one or more functional cross-linking agents and one or more secondary cross-linking agents (e.g., one or more functional cross-linking agents and/or one or more secondary cross-linking agents as described in sections 2.1 and 2.2);

(iii) one or more functional monomers and one or more functional crosslinkers (e.g., one or more functional monomers and/or one or more functional crosslinkers described in sections 2.1 and 2.2);

(iv) one or more functional monomers, one or more functional crosslinkers, and one or more secondary crosslinkers (e.g., one or more functional monomers and/or one or more functional crosslinkers and/or secondary crosslinkers as described in sections 2.1 and 2.2).

Then, a polymerization initiator (e.g., a solution of a free radical initiator, as described in section 2.3) in an amount of methanol or other solvent is combined with the mixture to initiate polymerization. The mixture is maintained at an appropriate temperature (e.g., 60 ℃) for a period of time to allow polymerization to occur (e.g., about 16 hours).

Optionally performing one or more of the following steps after the polymerizing:

the molecularly imprinted polymer is pulverized and/or ground to a powder (e.g., after cooling the polymerization mixture to room temperature). The comminution and/or grinding can be carried out using, for example, a mill (e.g., a roll mill or a ball mill).

Selecting the desired particle size, for example by filtering the powder (e.g., through one or more sieves as described in section 2). In some embodiments, filtering comprises passing the powder through one or more sieves, such as one or more of a 300 mesh sieve, a 500 mesh sieve, a 900 mesh sieve, and an 1800 mesh sieve.

Washing the molecularly imprinted polymer (with solvent) to remove template and/or unreacted reagents. Washing may be exemplified by hot methanol and soxhlet extraction washing with different solvents. Testing the extract from the soxhlet extraction confirmed that no template was detected.

Drying the molecularly imprinted polymer in one or more steps, (e.g. in an oven at 100 ℃, for about 15 hours and/or under vacuum, e.g. at 60 ℃, for about 2 days).

3. Acetate-binding molecularly imprinted polymer

One aspect of the present invention provides an acetate binding molecularly imprinted polymer. The acetate binding molecularly imprinted polymers of the present invention may be one or more functional molecules as described in section 2. Exemplary acetate binding molecularly imprinted polymers are described in section 3, examples and specific examples.

In some embodiments, the acetate binding molecularly imprinted polymer comprises or consists essentially of N, N' -methylenebis (acrylamide) (MBA) and Ethylene Glycol Dimethacrylate (EGDA). In some embodiments, MBA and EGDA together represent at least 80% of the dry weight of the molecularly imprinted polymer (e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%), and the remaining dry weight is, if any, one or more additional components, such as one or more monomers, other crosslinkers, and/or residual template molecules. The ratio of MBA to EGDA may vary from 1:5 to 5:1 (e.g., 1:5 to 1:1 or 1:1 to 5: 1). For example, the ratio may be 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 2:5, 3:5, 4:5, 6:5, and may be any range defined by any two of the ratios described above. In some embodiments, the ratio is 1:1. In some particular embodiments, the ratio is 1: 1.05. As detailed in the examples, it has been found that acetate binding molecularly imprinted polymers comprising MBA and EGDA have particularly superior properties compared to other acetate binding molecularly imprinted polymers.

The acetate binding molecularly imprinted polymers of the present invention preferably have an ability to bind acetate in water at least 5mg acetate per gram of molecularly imprinted polymer (e.g., at least 10mg acetate per gram of molecularly imprinted polymer, at least 20mg acetate per gram of molecularly imprinted polymer, at least 30mg acetate per gram of molecularly imprinted polymer, or at least 35mg acetate per gram of molecularly imprinted polymer). In some embodiments, the acetate binding molecularly imprinted polymers of the invention have an ability to bind acetate in water from 5mg to 40mg of acetate per gram of molecularly imprinted polymer (e.g., 10mg to 40mg, 10mg to 30mg, 10mg to 20mg, 20mg to 40mg, 20mg to 30mg, 30mg to 40 mg). Acetate binding capacity can be measured, for example, by ion chromatography. The following assay can be used to measure acetate binding capacity:

10mg of test molecularly imprinted polymer was incubated in sodium acetate solution (100mM, 2mL) for 2 hours.

After removal of the molecularly imprinted polymer from the solution by centrifugation, the remaining solution was analyzed for acetate content using an ion chromatography system equipped with a guard column (4X 50mm), Dionex IonPac^TMAS22 analytical columns (4X 250mm) and a serial conductivity detector (Dionex, ICS-1600). An aqueous solution of 4.5mM sodium carbonate and 1.4mM sodium bicarbonate at a flow rate of 1.0mL/min was used as the mobile phase.

Identification and quantification of the chromatographic peak of acetate with reference to the retention time of the acetic acid standard. The acetate concentration was quantified using an external calibration curve with at least 5 calibration points.

The acetate binding molecularly imprinted polymers of the present invention preferably have a higher selectivity for acetate than chloride, as reflected, for example, by measuring acetate binding and chloride binding capacity in sodium acetate and sodium chloride solutions. The following analysis can be used to compare the selectivity of molecularly imprinted polymers for acetate and chloride:

10mg of test molecularly imprinted polymer was incubated in 2mL of a solution of sodium acetate (10mM) and sodium chloride (10mM) for 2 hours.

After removal of the molecularly imprinted polymer from the solution by centrifugation, the remaining solution was analyzed for acetic acid and chloride content using an ion chromatography system equipped with a guard column (4x 50mm), a Dionex IonPacTM AS22 analytical column (4x 250mm) and a serial conductivity detector (Dionex, ICS-1600). An aqueous solution of 4.5mM sodium carbonate and 1.4mM sodium bicarbonate at a flow rate of 1.0mL/min was used as the mobile phase.

In some embodiments, the molecularly imprinted polymers disclosed herein have at least 10-fold affinity for acetate as compared to 10-100-fold affinity for chloride (e.g., 10-100-fold, 10-50-fold, 10-20-fold, 25-100-fold, 25-50-fold, 50-100-fold, or 50-75-fold affinity for acetate as compared to chloride).

In some embodiments, the acetate binding molecularly imprinted polymers of the present invention (a) are imprinted using a template in which acetic acid is the only organic moiety and/or (b) use a template having a molecular weight of no more than 200g/mol, no more than 175g/mol, no more than 150g/mol, no more than 125g/mol, or no more than 100g/mol and/or (c) have a higher selectivity for acetate than acetate binding organic molecules. In some embodiments, the molecularly imprinted polymers of the invention have at least a 10-fold (e.g., 10 to 100-fold) affinity for acetate (e.g., 10 to 100-fold, 10 to 50-fold, 10 to 20-fold, 25 to 100-fold, 25 to 50-fold, 50 to 100-fold, or 50 to 75-fold greater affinity for acetate than for an organic molecule). In some embodiments, the acetate binding organic molecule is 2-methyl-4-chlorophenoxyacetic acid, 2, 4-dichlorophenoxyacetic acid, 2,4, 5-trichlorophenoxyacetic acid, cortisone acetate, dexamethasone acetate, hydrocortisone acetate, betamethasone acetate 21, or phenoxyacetic acid. The above-described assay for comparing the selectivity of a molecularly imprinted polymer for acetate versus chloride may be adapted to measure the selectivity of a molecularly imprinted polymer for acetate versus another molecule (which may also be quantified by ion chromatography), for example, by replacing the chloride in the assay with a different molecule. For molecules that cannot be detected by ion chromatography, liquid chromatography-mass spectrometry can be used to quantify the selectivity of molecularly imprinted polymers.

Research shows that the acetate-binding molecularly imprinted polymer prepared from N, N' -Methylene Bisacrylamide (MBA) and Ethylene Glycol Dimethacrylate (EGDA) has surprisingly high acetate-binding capacity and high selectivity to acetate.

4. Formulations and pharmaceutical compositions

The present invention provides formulations comprising a population of molecularly imprinted polymer particles as described herein. Such formulations can have a high purity, for example, such a population can be at least 85% pure, at least 90% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, or more than 99% pure (e.g., 99.5% pure or 99.8% pure) or any range defined by the above values, such as 85% to 95% pure, 90% to 95% pure, 95% to 99% pure 97% to 99.5% pure, or 98% to 99.8% pure. Purity can be measured by methods such as infrared spectroscopy.

The formulations of the present invention preferably include particles that are large enough so that the particles are not absorbed from the gastrointestinal tract when orally administered (e.g., in some embodiments, the particles are at least 10 μm in diameter), and small enough so that they have a high capacity for the molecule of interest (e.g., in some embodiments, the particles are less than 100 μm or less than 50 μm in diameter). In some embodiments, the D (v,0.5) particle size of the molecularly imprinted polymer formulation of the invention is 10 μm to 50 μm (e.g., 10 μm to 40 μm, 10 μm to 30 μm, 10 μm to 20 μm, 15 μm to 50 μm, 15 μm to 40 μm, 15 μm to 30 μm, 15 μm to 25 μm, 15 μm to 20 μm, 20 μm to 50 μm, 20 μm to 40 μm, 20 μm to 30 μm, 30 μm to 50 μm, 30 μm to 40 μm, 40 μm to 50 μm, or any range defined by any two of the above values). In some embodiments, the molecularly imprinted polymer formulations of the invention have a D (v,0.5) particle size of from 15 μm to 25 μm (e.g., 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, or 25 μm). In other embodiments, the molecularly imprinted polymer formulations of the invention have a D (v,0.5) particle size of from 10 μm to 15 μm (e.g., 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, or 15 μm). D (v,0.5) is defined as the volume median diameter. The D (v,0.5) particle size can be measured using a laser particle size analyzer, such as BT-9300S laser particle size analyzer (Bettersize, China)

The size of a population of molecularly imprinted polymer particles may be selected by, for example, filtering the molecularly imprinted polymer through one or more sieves. For example, filtration through a 300 mesh screen may be used to provide (or remove) molecularly imprinted polymer particles smaller than 50 μm; filtration through a 500 mesh screen may be used to provide (or remove) molecularly imprinted polymer particles smaller than 30 μm; filtering through a 900 mesh screen can be used to provide (or remove) molecularly imprinted polymer particles smaller than 20 μm; filtering the screen through a 1800 mesh screen can be used to provide (or remove) molecularly imprinted polymer particles smaller than 10 μm.

The invention also provides pharmaceutical compositions comprising the molecularly imprinted polymers of the invention, e.g., acetate-binding molecularly imprinted polymers of the invention, and pharmaceutical compositions comprising the formulations of the invention. The pharmaceutical composition can be prepared into oral preparations. The pharmaceutical compositions of the present invention may be in liquid (e.g., suspensions or solutions) or solid dosage forms (e.g., capsules or tablets). The pharmaceutical composition may comprise one or more pharmacologically acceptable excipients.

Oral liquid dosage forms include suspensions and solutions, such as syrups, oral droplets, microemulsions or nanosuspensions. Liquid dosage forms may include a molecularly imprinted polymer and one or more liquid excipients, such as water, saline, ethanol, propylene glycol, 1, 3-butylene glycol, oils (e.g., cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, and mixtures thereof), glycerol, polyethylene glycols, and combinations thereof.

Oral solid dosage forms include capsules, tablets (such as orally disintegrating tablets, chewable tablets, dispersible tablets, effervescent tablets, and the like), powders, granules, oral tablets, chewing gums, and buccal tablets. In such solid dosage forms, the molecularly imprinted polymer may be mixed with one or more excipients, such as one or more starches, lactose, dextrose, sucrose, glucose, mannitol, silicic acid, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia, agar, calcium carbonate, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. Capsule dosage forms may comprise hard or soft shells, including, for example, gelatin, hydroxypropylmethylcellulose, or pullulan. Solid dosage forms, such as dispersible tablets, effervescent tablets, powders and granules, can be dissolved or dispersed in a liquid or added to a food product prior to administration.

5. Therapeutic uses

The molecularly imprinted polymers of the invention may be used in the manufacture of a medicament, for example, as described in the specific examples, pharmaceutical compositions for use in a method of sequestering a target molecule in the gastrointestinal tract of a subject.

The molecularly imprinted polymers, formulations and pharmaceutical compositions of the invention may be used to sequester target molecules, e.g., microbially-derived metabolites such as acetate or other target molecules described herein, in the gastrointestinal tract of a subject (e.g., a human subject). For example, acetate-binding molecularly imprinted polymers of the invention may be used to treat a subject diagnosed with or at risk of a disease associated with acetate accumulation, such as metabolic syndrome and/or obesity. In some embodiments, acetate binding molecularly imprinted polymers of the invention may be administered to a subject to reduce the weight of the subject.

The molecularly imprinted polymers, formulations and pharmaceutical compositions may be administered orally. For example, the molecularly imprinted polymer, formulation or pharmaceutical composition may be mixed with a liquid (e.g., water) or with a food product prior to administration.

In some embodiments, the molecularly imprinted polymers, formulations, and pharmaceutical compositions of the invention may be administered daily, such as once daily or multiple times daily (e.g., per meal). The amount of molecularly imprinted polymer administered per day may vary from 100mg to 500g (e.g., 100mg to 1g, 1g to 5g, 1g to 10g, 5g to 15g, 10g to 25g, 20g to 50g, 20g to 100g, 50g to 200g, 100g to 500g, 200g to 500g, or 300g to 500 g).

Examples

Example 1 acetate binding molecularly imprinted polymers

Synthesis and characterization

A mixture of acrylamide (15.8g, 0.222mol) (monomer), N-methylenebis (acrylamide) (42.0g, 0.273mol) (crosslinker), sodium benzoate (5.0g, 0.034mol) (template molecule) was heated to 70 ℃ in dimethyl sulfoxide (150mL) and degassed with argon for 15 minutes of Janus. Subsequently, 2' azobisisobutyronitrile (50mg, 0.3mmol) was added to the mixture as a radical initiator. The resulting mixture was held at 70 ℃ for 16 hours during which time a molecularly imprinted polymer was formed.

The molecularly imprinted polymer was crushed and washed with hot methanol and water. Further grinding and passing through a sieve to obtain the molecular engram polymer particles with the particle size of less than 50 μm. The molecularly imprinted polymer was washed with methanol, water and acetone by soxhlet extraction until no reaction residue was detected by infrared spectroscopy. Before conducting the in vivo study, the molecularly imprinted polymer was dried under vacuum at 70 ℃ for 5 days. Infrared Spectrum (Potassium bromide tablet, v/cm)^-1): 2940(m), 2866(m), 1660(vs), 1529(vs), 1450(m), 1417(w), 1385(m), 1340(w), 1290(m), 1217(m), 1112(m), 985 (w). Acetate binding affinity: 10.2mg/g in water.

In vivo Activity Studies

The effect of acetate-binding molecularly imprinted polymers in vivo was studied using a diet-induced obesity mouse model. Mice were fed a customized High Fat Diet (HFD) from C57BL/6 (Envigo, td.06414) with or without acetate-binding molecularly imprinted polymers. HFD is 5.1kcal/g, which contains protein 23.5%, carbohydrate 27.3%, and fat 34.3%. Approximately 60% of the calories are from fat. A total of 24C 57BL/6 mice, 15-17 weeks old, were free to eat HFD for 5 weeks prior to study initiation. After 5 weeks, mice were randomized into 3 groups. Group a (n ═ 9) mice were fed with HFD mixed with acetate-binding molecularly imprinted polymer at 15% total weight of diet. Group B (n-9) mice were mixed with HFD as a control polymer, using polypropylene powder (average particle size about 40 μm) at 15% of total feed weight. Group C (n ═ 6) was continued with HFD.

Body weight and food intake were measured 5 times per week. All mice were sacrificed at the end of the experiment and their organs, feces and blood were collected to evaluate their toxicity and physiological effects. The experimental schedule is shown in figure 4. Total cholesterol levels and toxicity as judged by liver function, kidney function and expression of TNF-alpha, IL-1a, IL-6 immune genes by reverse transcription polymerase chain reaction (RT-PCR) analysis.

Results

Body weight was steadily increased in a similar manner in all mice during the 5 week HFD period prior to the study period. The average weight of the animals in the group A is 7.77 +/-1.79 g, the average weight of the animals in the group B is 7.80 +/-1.52 g, and the average weight of the animals in the group C is 6.75 +/-1.49 g (p is 0.362). After the 4-week study period, mice fed HFD mixed with acetate-binding molecularly imprinted polymer lost weight compared to the control polymer (polypropylene) or HFD without polymer in group a. The average body weight of the animals is shown in fig. 5A. Overall, the mice in group A lost 0.88. + -. 1.27 grams in weight, while the mice in group B gained 2.90. + -. 1.13 grams in weight, and the mice in group C gained 2.11. + -. 0.34 grams in weight (FIG. 5B). The kruskal wallis test showed significant weight change between the two groups (p ═ 0.0004), and the mannwithney U test also showed significant weight loss in group a compared to group B (adjusted p ═ 0.0003) and group C (adjusted p ═ 0.025). There was no significant change in body weight in the two control groups (group B and group C, corrected p ═ 1.000). Considering the weight of the polymer, net fed weights were similar in the three groups of mice (group a: 2.56 ± 0.42 g/mouse/day, group B: 2.44 ± 0.31 g/mouse/day, group C: 2.54 ± 0.26 g/mouse/day, p ═ 0.477).

Group A Total Cholesterol is lower than those of groups B and C (FIG. 5C)

There were no significant differences in liver function, kidney function and TNF-alpha, IL-1a, IL-6 expression between the two groups (FIGS. 5D-5F). Example 2 second Generation acetate binding molecularly imprinted polymers

Materials and methods

Materials and reagents

Acrylamide, Ethylene Glycol Dimethacrylate (EGDA), Divinylbenzene (DVB), pentaerythritol triacrylate (PETA),Trimethylolpropane trimethacrylate (TMPTMA), acryloxyethyltrimethylammonium chloride (NAAC), N-methylenebis (acrylamide) (MBA), sodium persulfate, ammonium persulfate, potassium acetate from J&K Chemicals Ltd, N-isopropylacrylamide (NIPA) and N-ethylacrylamide (NEA) from Acros Organics Chemical Company. Sodium acetate from Riedel-de

Sodium chloride, sodium bicarbonate and sodium chloride were obtained from Uni Chem inc. All solvents including acetone, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, methanol and ethanol were analytical reagent grade and used without further purification. Milli-Q water was prepared using a Millipore Milli-Q gradient A10 system.

General molecular imprinted polymer Synthesis (Small Scale)

A mixture of functional monomer/crosslinker, crosslinker and template was added in a ratio of 4:10:1 to a 20mL tube containing 3mL of solvent (e.g., tetrahydrofuran, dimethylamide and/or methanol) (FIG. 6). The resulting mixture was degassed by bubbling through argon for 15 minutes and heated to 60 ℃. Thereafter, 0.5ml of a radical initiator solution was added dropwise to the reaction mixture to initiate polymerization. The reaction mixture was kept at 60 ℃ for a further 16 hours. After cooling to room temperature, the resulting molecularly imprinted polymer is crushed into small pieces and finely crushed into powder. After washing with hot methanol, the powder was further washed with methanol (3 days), milli-Q water (3 days) and acetone (1 day) by soxhlet extraction. The extract of the Soxhlet extraction solution was examined to confirm that no reagent residue was detected. The powder was then dried in an oven at 80 ℃ overnight. Further drying was achieved by vacuum drying at 60 ℃ for 2 days.

Synthesis of P1-P9

In initial studies, it was found that polymers crosslinked by DVB, PETA, TMPTMA exhibited very low acetate binding affinity. Without being bound by theory, it is believed that the weak binding affinity may be due to weak binding of these cross-linkers to the counter cation, and that acetate binding is also significantly reduced. For polymers containing NAAC, the reaction produces a gel rather than a polymer. Continuing with the initial study, polymers based on different combinations of acrylamide, MBA and EGDA were further studied (P1-P9). Their syntheses are summarized in FIGS. 7A-7B Table 1 summarizes the starting materials used to synthesize P1-P9.

TABLE 1

Detailed Synthesis procedure for P6

In a 20mL test tube containing 3mL of methanol, a mixture of 0.46g acrylamide (functional monomer), 2.5 g N, N' -methylenebis (acrylamide) (MBA) (functional crosslinker), and 0.134 g sodium acetate was added. The resulting mixture was degassed by bubbling with argon for 15 minutes and heated to 70 ℃. At this temperature, a suspension of 40mg of ammonium persulfate in 0.5ml of methanol was added in a dropwise manner to start the polymerization. The reaction mixture was held at 70 ℃ for 16 hours. The resulting polymer was crushed, washed with hot methanol, and finely ground into a powder. To exclude polymers larger than 40 μm, the molecularly imprinted polymer was filtered through a 300 mesh screen. The powder was washed with methanol (5 days), milli-Q water (5 days) and ethanol (2 days) by soxhlet extraction. After washing, the powder was dried in an oven at 80 ℃ overnight and then dried under vacuum at 60 ℃ for 2 days.

Detailed Synthesis procedure for P8

In a 20mL test tube containing 3mL of methanol, a mixture of 0.46g acrylamide (functional monomer), 2.7g EGDA (second crosslinking agent), and 0.132g sodium acetate as a template was added. The resulting mixture was degassed by bubbling with argon for 15 minutes and heated to 80 ℃. A solution of 20mg of ammonium persulfate in 0.5ml of methanol was then added in a dropwise manner to start the polymerization. Thereafter, the reaction mixture was kept at 80 ℃ for another 16 hours. The resulting polymer was crushed, washed with hot methanol, and finely ground into a powder. To exclude polymers larger than 40 μm, the molecularly imprinted polymer was filtered through a 300 mesh screen. The powder was further washed with methanol (3 days), milli-Q water (3 days) and acetone (1 day) by soxhlet extraction. After washing, the powder was dried in an oven at 80 ℃ overnight and then dried under vacuum at 60 ℃ for 2 days.

P9₃Detailed synthesis procedure of

A20 mL test tube containing 3mL of methanol was charged with a mixture of 2g of (MBA) (functional crosslinking agent), 2.7g of EGDA (second crosslinking agent), and 0.4g of potassium acetate as a template. The resulting mixture was degassed by bubbling with argon for 15 minutes and then heated to 70 ℃. At this temperature, a suspension of 40mg of ammonium persulfate in 0.5ml of methanol was added in a dropwise manner to start the polymerization. The reaction mixture was kept at 70 ℃ for a further 16 hours. The resulting polymer was crushed, washed with hot methanol, and finely ground into a powder. To exclude polymers larger than 40 μm, the molecularly imprinted polymer was filtered through a 300 mesh screen. The powder was washed with methanol (5 days), milli-Q water (5 days) and ethanol (2 days) by soxhlet extraction. After washing, the powder was dried in an oven at 80 ℃ overnight and then dried under vacuum at 60 ℃ for 2 days.

Large Scale P9₃Detailed synthesis procedure (P9)_L)

In a 500mL round bottom flask containing 60mL of methanol, a mixture of 40g of MBA (functional crosslinker), 54g of EGDA (second crosslinker) and 8g of potassium acetate was added. The resulting mixture was degassed by bubbling with argon for 15 minutes and then heated to 70 ℃. At this temperature, a suspension of 400mg of ammonium persulfate in 5ml of methanol was slowly added to start the polymerization. The reaction mixture was kept at 70 ℃ for 16 hours. The resulting polymer was pulverized, washed with hot methanol, and finely ground into powder with a grinder. The powder was passed through a 300 mesh screen to exclude polymers larger than 40 μm. The powder was washed with methanol (5 days), milli-Q water (5 days) and ethanol (2 days) using soxhlet extraction. After washing, the powder was dried in an oven at 80 ℃ for 15 hours and then further dried under vacuum at 60 ℃ for 2 days.

Physical measurement and instrumentation

Infrared spectra were obtained on potassium bromide pellets using a Perkin-Elmer Spectroscopy 100FTIR spectrophotometer. Thermogravimetric analysis (TGA) was performed on PerkinElmer STA 6000. Thermogravimetric analysis was performed using 5-10mg of sample under nitrogen atmosphere at a temperature ramp rate of 5 ℃/min between 30 ℃ and 700 ℃.

Acetate binding affinity study

Binding affinity studies were performed by incubating 10mg of molecularly imprinted polymer in sodium acetate solution (100mM, 2mL) for 2 hours. After removal of the molecularly imprinted polymer from the solution by centrifugation, the acetate content was analyzed by ion chromatography, equipped with a guard column (4x 50mm), a Dionex IonPacTM AS22 analytical column (4x 250mm) and a serial conductivity detector (Dionex, ICS-1600). The mobile phase was 4.5mM sodium carbonate and 1.4mM aqueous sodium bicarbonate at a flow rate of 1.0 mL/min. The chromatographic peak of acetic acid was identified and quantified with reference to the retention time of the acetic acid standard. The acetate concentration was quantified using an external calibration curve with at least 5 calibration points.

In vivo studies

An in vivo study similar to example 1 was performed. In this study, obese mice (5 per group) were induced with HFD for 4 weeks. After a weight gain period of 4 weeks, molecularly imprinted polymer-P9 was added_LAdded to their feed in 0%, 1%, 5%, 15% and 25% increments by volume, respectively. Body weight, daily water consumption and daily food consumption were measured. General condition and health of mice were monitored. The results of the in vivo studies are shown in FIG. 9 (molecularly imprinted polymer P9)_L) And FIG. 11 (molecularly imprinted polymer P8).

Mutagenicity test

Study P9_LThe possibility of inducing the point mutation of Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli WP2 uvrA is induced. The experimental design followed the OECD chemical detection guide-471, bacterial back-mutation assay (Ames assay).

Results and discussion

Yield, infrared spectrum, thermal stability

The yields and infrared spectral absorption data for P1-P9 are shown in Table 2.

TABLE 2

P6, P8 and P9 were investigated by thermogravimetric analysis_LThermal stability of (2). As shown by the TGA thermograms of fig. 8A-8C, all the tested molecularly imprinted polymers showed high thermal stability, measured up to about 240 ℃ without decomposition, which is reflected by very small weight loss. When the temperature was increased above 250 ℃, the weight of these polymers began to drop, indicating that the polymers decomposed. When the temperature is increased to about 315-330 ℃, the weight loss rate is increased sharply. When the temperature reaches 475 ℃, less than 5% of the original weight of the molecularly imprinted polymer remains. This confirms the thermal stability of these polymers at physiological temperatures.

Acetate binding Properties

As previously mentioned, polymers crosslinked by DVB, PETA and TMPTMA exhibit very low acetate binding affinity, again without being bound by theory, due to the weak binding of these crosslinkers to the mating cations. The acetate binding capacity of several molecularly imprinted polymers was determined by ion chromatography and the results are shown in tables 3-4. P6 prepared in example 2 showed lower binding capacity compared to the molecularly imprinted polymer in example 1 prepared using the same building block in DMSO using AIBN as initiator. For the molecularly imprinted polymer prepared by taking methanol as a solvent and persulfate as an initiator, P9_LThe binding capacity to acetate was highest (table 3). Therefore, at P9_LLarge scale synthesis and in vivo animal studies to determine dose-response relationships.

For an insight into the solvent media pairs P6, P8 and P9_LThe effect of binding capacity in methanol was determined for P6, P8 and P9_LAcetate binding capacity in methanol. Without being bound by theory, it is believed that the acetate binds more strongly in methanol due to its weaker solvation in methanol. P9 with different particle sizes is prepared_LAnd their acetate binding capacity was determined. The results (Table 4) show that polymers with smaller particle size have higher binding capacity.

TABLE 3

Polymer and method of making same	Binding force of acetate in Water (mg/g)	Binding force of acetate in methanol (mg/g)
			P1	2.42
P2	12.32
			P3	8.20
P4	7.82
			P6	7.19	39.67
P8	10.37	42.27
			P9_L	33.47	95.16

TABLE 4

In vivo testing

Molecularly imprinted polymer P9_LThe results of the primary endpoint (weight) of the in vivo test are shown in figure 9. The weight of the mice gradually lost with the increase of the addition amount of the molecularly imprinted polymer. At administration of P9_LNo significant hepatotoxicity (indicated by the liver enzymes ALT and AST) or mucosal damage (indicated by iFABP and FIT) was observed in the mice of (a).

Acetate-binding molecularly imprinted polymer-P8 was also evaluated in vivo. The results are shown in FIG. 11. Comparing FIGS. 5A, 9 and 11, P9_LIt appeared to be more effective in reducing body weight than the molecularly imprinted polymers of example 1 and P8.

Mutagenicity test

Under the conditions of the test, no P9 was found_LHas mutagenesis effect on strains TA98, TA100, TA1535 and TA1537 of salmonella typhimurium and strain WP2 uvrA of escherichia coli.

Example 3 other acetate-binding molecularly imprinted polymers

Synthesis of molecularly imprinted polymers

Several different acetate binding molecularly imprinted polymers were prepared according to the following general synthetic route.

The mixture consisting of the functional molecule, the second crosslinker (when used) and the template molecule is dissolved in a solvent at 60 ℃ to 80 ℃ and degassed by bubbling with argon or nitrogen for 15 minutes. Thereafter, methanol or other solvent is added to the mixture to initiate polymerization. The reaction mixture was held at 60 ℃ for 16 hours. After cooling to room temperature, the resulting polymer was pulverized into small pieces, finely pulverized into powder, and filtered through a sieve to collect imprinted polymer having a desired particle size. After washing, the powder was dried in an oven at 100 ℃ for 15 hours and then further dried under vacuum at 60 ℃ for 2 days. The washing of the molecularly imprinted polymer is usually performed by hot methanol followed by soxhlet extraction with different solvents.

P-OAc-1

Molecularly imprinted polymers binding to acetate were prepared with the following reagents: functional crosslinking agent: 40g N, N-methylenebis (acrylamide) (MBA); a second crosslinking agent: 54g Ethylene Glycol Dimethacrylate (EGDA); template molecule: 8g of potassium acetate; solvent: 60mL of methanol; initiator: 0.3g ammonium persulfate. Yield: 60 percent. Infrared Spectrum (Potassium bromide, cm)^–1): 1156(s), 1246(m), 1384(m), 1460(w), 1526(m), 1658(s), 1725(s), 2852(w), 2920(w), 2956(m), 2991(w), 3436 br(s). Acetate binding capacity: 33.5mg/g water; 95.2mg/g in methanol.

P-OAc-2

Molecularly imprinted polymers bound to acetate were prepared with the following reagents: functional monomer: 4.6g of acrylamide; a second crosslinking agent: 27g of EGDA; template molecule: 1.32g of sodium acetate; solvent: 30mL of DMSO; initiator: 0.2g AIBN. Yield: 52 percent. Infrared Spectrum (Potassium bromide, cm)^–1): 954(w), 1051(w), 1163(w), 1262(m), 1389(w), 1459(m), 1639(w), 1673(m), 1728(vs), 2895(w), 2958(m), 2999(m), 3464 br(s). Acetate binding: 10.3mg/g water; 42.3mg/g in methanol.

P-OAc-3

Molecularly imprinted polymers binding to acetate were prepared with the following reagents: functional crosslinking agent: 5.0g of 1, 3-bis (4- (allyloxy) phenyl) urea; a second crosslinking agent: 13.2g of 1, 2-diallyloxybenzene; a second crosslinking agent: 10.9g divinylbenzene; template molecule: 1.55g of potassium acetate; solvent: 45mL of methanol: dimethylformamide (1: 1); initiator: 0.5g of dimethyl azodiisobutyrate. Yield: and 55 percent.

P-OAc-4

Molecularly imprinted polymers binding to acetate were prepared with the following reagents: functional crosslinking agent: 4.1g of 1, 3-bis (4-vinylphenyl) urea; a second crosslinking agent: 13.2g of 1, 2-diallyloxybenzene; a second crosslinking agent: 10.9g divinylbenzene; template molecule: 1.55g of potassium acetate; solvent: 45mL of methanol: dimethylformamide (1: 1); initiator: 0.5g of dimethyl azodiisobutyrate. Yield: 58 percent.

P-OAc-5

Molecularly imprinted polymers binding to acetate were prepared with the following reagents: functional crosslinking agent: 5g of 1, 3-diallylurea; a second crosslinking agent: 6.9g of 1, 2-diallyloxybenzene; a second crosslinking agent: 5.6g of 1, 3-diisopropenylbenzene; template molecule: 1.7g of potassium acetate; solvent: 20mL of methanol; initiator: 0.3g of dimethyl azodiisobutyrate. Yield: and 64 percent.

P-OAc-6

Molecularly imprinted polymers binding to acetate were prepared with the following reagents: functional crosslinking agent: 5g of 1, 3-diallylurea; a second crosslinking agent: 9.4g of 1, 3-diisopropenylbenzene; template molecule: 1.7g of potassium acetate; solvent: 20mL of methanol; initiator: 0.3g of dimethyl azodiisobutyrate. Yield: 73 percent.

P-OAc-7

Molecularly imprinted polymers binding to acetate were prepared with the following reagents: functional crosslinking agent: 5g of 1, 3-diallylurea; a second crosslinking agent: 11.3g of 1, 2-diallyloxybenzene; template molecule: 1.7g of potassium acetate; solvent: 20mL of methanol; initiator: 0.3g of dimethyl azodiisobutyrate. Yield: 62 percent.

5.3.9.P-OAc-8

Molecularly imprinted polymers binding to acetate were prepared with the following reagents: functional crosslinking agent: 5g of 1, 3-diallylurea; a second crosslinking agent: 11.6g of divinylbenzene; template molecule: 1.7g of potassium acetate; solvent: 20mL of methanol; initiator: 0.2g of dimethyl azodiisobutyrate. Yield: 60 percent.

P-OAc-9

Molecularly imprinted polymers binding to acetate were prepared with the following reagents: functional crosslinking agent: 5g of 1, 3-diallylurea; a second crosslinking agent: 7.6g of divinyl succinate; template molecule: 1.7g of potassium acetate; solvent: 15mL of methanol; initiator: 0.2g of dimethyl azodiisobutyrate. Yield: 65 percent of

P-OAc-10

Molecularly imprinted polymers binding to acetate were prepared with the following reagents: functional crosslinking agent: 5g of 1, 3-diallylurea; a second crosslinking agent: 15g of divinyl succinate; template molecule: 1.7g of potassium acetate; solvent: 15mL of methanol; initiator: 0.2g of dimethyl azodiisobutyrate. Yield: 75 percent.

Example 4 comparison of acetate-binding molecularly imprinted polymers

Various acetate binding molecularly imprinted polymers were compared. A summary of the components, reaction conditions and properties is shown in table 5. A plurality of acetate-binding molecularly imprinted polymers with high binding capacity are identified. Compared with other acetate-binding molecularly imprinted polymers, P9_LHas better acetate binding capacity and selectivity to chloride ions.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The following examples illustrate specific embodiments of the invention:

1. a molecularly imprinted polymer (molecularly imprinted polymer) capable of binding acetate.

2. The molecularly imprinted polymer of example 1, which is capable of binding acetate in the gastrointestinal tract of a mammal.

3. The molecularly imprinted polymer of example 1, which is capable of binding acetate in the human gastrointestinal tract.

4. A molecularly imprinted polymer of example 2 or example 3, wherein acetate is produced by the gut microbiota.

5. The molecularly imprinted polymer of any one of embodiments 1 to 4, comprising one or more functional molecules, wherein each functional molecule is independently a functional crosslinker or a functional monomer.

6. The molecularly imprinted polymer of embodiment 5, wherein one or more of the functional molecules have been polymerized and crosslinked.

7. The molecularly imprinted polymer of embodiment 5 or embodiment 6, wherein the one or more functional molecules comprise one or more functional cross-linkers.

8. The molecularly imprinted polymer of embodiment 7, wherein the one or more functional cross-linkers comprise one or more amide-containing cross-linkers.

9. The molecularly imprinted polymer of embodiment 8, wherein the one or more functional cross-linkers comprise or comprise N, N' -methylenebis (acrylamide) (MBA).

10. The molecularly imprinted polymer of any one of embodiments 7 to 9, wherein the one or more functional cross-linkers comprise one or more urea-containing cross-linkers.

11. A molecularly imprinted polymer of embodiment 10, wherein the one or more functional cross-linking agents comprise or consist of 1, 3-bis (4-vinylphenyl) urea, 1, 3-bis (4 (allyloxy) phenyl) urea, 1, 3-diallylurea, or a combination thereof.

12. The molecularly imprinted polymer of any one of embodiments 5 to 11, wherein the functional molecule does not comprise any functional monomer.

13. The molecularly imprinted polymer of any one of embodiments 5 to 11, wherein the functional molecule comprises one or more functional monomers.

14. A molecularly imprinted polymer of embodiment 13, wherein the one or more functional monomers comprise one or more acrylamides.

15. A molecularly imprinted polymer of embodiment 14, wherein the one or more acrylamides comprise acrylamide, N-alkylacrylamide, methacrylamide, or a combination thereof.

16. The molecularly imprinted polymer of embodiment 14 or embodiment 15, wherein the one or more acrylamides comprise or consist of acrylamide.

17. The molecularly imprinted polymer of embodiment 15 or embodiment 16, wherein the one or more acrylamides comprise or consist of N-methacrylamide, N-ethylacrylamide, N-isopropylacrylamide, N-methyl methacrylate, N- (3-aminopropyl) methacrylamide, N- (2-oxyethyl) -2-acrylamide, N- (2-aminopyridine) methacrylamide, or a combination thereof.

18. A molecularly imprinted polymer of any one of embodiments 13 to 17, wherein the one or more monomers comprise or consist of N-vinylacetamide, N- [ [ [3- (vinylsulfonyl) -1-acetonyl ] amino ] methyl ] -2-acrylamide, 4-vinylbenzamide, N-alkyl- (4-vinylbenzamide), N' -diethyl (4-vinylphenyl) amide, hydroxy-substituted styrene, amide-substituted styrene, N- (diaminoethylene) -2-methylpropen-2-enamine, N-allylurea, 1-allyl-2-thiourea, or a combination thereof.

19. The molecularly imprinted polymer of any one of embodiments 5 to 18, comprising one or more functional molecules and one or more crosslinkers other than any functional crosslinker (such one or more crosslinkers are referred to as "second crosslinker")

20. A molecularly imprinted polymer of embodiment 19, wherein the one or more second crosslinking agents comprise or consist of Ethylene Glycol Dimethacrylate (EGDA), ethylene glycol diacrylate, 1, 2-diallyloxybenzene, divinylbenzene, 1, 3-diisopropenylbenzene, divinylsuccinic acid, 1, 3-divinyltetramethyldisiloxane, tri (ethylene glycol) divinyl ether, di (ethylene glycol) divinyl ether, trimethylolpropane trimethacrylate, pentaerythritol triacrylate, or combinations thereof.

21. A molecularly imprinted polymer of embodiment 20, wherein the one or more second cross-linking agents comprise or consist of EGDA.

22. The molecularly imprinted polymer of any one of embodiments 19 to 21, wherein the molar ratio of the functional molecule to the second crosslinking agent is 1:5 to 5: 1.

23. A molecularly imprinted polymer of embodiment 21, wherein the molar ratio of the functional molecule to the second crosslinking agent is 1:5 to 1:1

24. A molecularly imprinted polymer of embodiment 21, wherein the molar ratio of the functional molecule to the second crosslinking agent is 1:1 to 5:1

25. A molecularly imprinted polymer of embodiment 21, wherein the molar ratio of the functional molecule to the second crosslinking agent is 1:1 to 4:5

26. A molecularly imprinted polymer of embodiment 25, wherein the molar ratio of the functional molecule to the second crosslinking agent is 1:1.05

27. The molecularly imprinted polymer of any one of examples 5 to 18, except as dependent on example 12, includes the functional monomer and the functional crosslinker and no second crosslinker.

28. A molecularly imprinted polymer of embodiment 27, wherein the molar ratio of functional monomer to functional crosslinker is 1:5 to 5: 1.

29. A molecularly imprinted polymer of embodiment 28, wherein the molar ratio of functional monomer to functional crosslinker is 1:5 to 1:1.

30. A molecularly imprinted polymer of embodiment 28, wherein the molar ratio of functional monomer to functional crosslinker is 1:1 to 5: 1.

31. The molecularly imprinted polymer of example 1, comprising N, N' -methylenebis (acrylamide) (MBA) and Ethylene Glycol Dimethacrylate (EGDA).

32. A molecularly imprinted polymer of embodiment 31, wherein the molar ratio of N, N' -methylenebis (acrylamide) (MBA) to EGDA is 1:5 to 5: 1.

33. A molecularly imprinted polymer of embodiment 32, wherein the molar ratio of N, N' -methylenebis (acrylamide) (MBA) to EGDA is 1:1 to 4: 5.

34. A molecularly imprinted polymer of embodiment 33, wherein the molar ratio of N, N' -methylenebis (acrylamide) (MBA) to EGDA is 1: 1.05.

35. The molecularly imprinted polymer of example 1, which has an IR peak corresponding to the IR peak of any one of the molecularly imprinted polymers shown in table 2.

36. A molecularly imprinted polymer according to any one of embodiments 1 to 35, wherein the molecularly imprinted polymer has an acetate binding capacity of at least 5mg acetate per g molecularly imprinted polymer in water.

37. A molecularly imprinted polymer according to any one of embodiments 36, wherein the molecularly imprinted polymer has an acetate binding capacity of 5mg acetate per g molecularly imprinted polymer to 40mg acetate per g molecularly imprinted polymer in water.

38. The molecularly imprinted polymer of example 36 or example 37, wherein the molecularly imprinted polymer has a binding capacity of at least 10mg acetate per g of molecularly imprinted polymer in water.

39. The molecularly imprinted polymer of example 36 or example 37, wherein the molecularly imprinted polymer has a binding capacity of at least 20mg acetate per g of molecularly imprinted polymer in water.

40. The molecularly imprinted polymer of example 36 or example 37, wherein the molecularly imprinted polymer has a binding capacity of at least 30mg acetate per g of molecularly imprinted polymer in water.

41. The molecularly imprinted polymer of embodiment 36 or embodiment 37, wherein the molecularly imprinted polymer has a binding capacity of at least 35mg acetate per g of molecularly imprinted polymer in water.

42. A molecularly imprinted polymer according to any one of embodiments 36 to 41, wherein the acetate binding capacity is determined by ion chromatography.

43. A molecularly imprinted polymer of example 42, wherein acetate binding capacity is determined by ion chromatography as described in section 3.

44. The molecularly imprinted polymer of any one of examples 1 to 43, having an affinity for acetate that is greater than that for chloride.

45. The molecularly imprinted polymer of example 44, which has a greater affinity for acetate than chloride as determined by ion chromatography.

46. A molecularly imprinted polymer of example 45, having greater affinity for acetate than chloride as determined by ion chromatography as described in section 3.

47. The molecularly imprinted polymer of any one of embodiments 44 to 46, wherein the affinity for acetate is 10 to 100 times greater than the affinity for chloride.

48. A molecularly imprinted polymer of example 47, wherein the affinity for acetate is 10 to 50 times that for chloride.

49. A molecularly imprinted polymer of example 47, wherein the affinity for acetate is 10 to 20 times that for chloride.

50. A molecularly imprinted polymer of example 47, wherein the affinity for acetate is 25 to 100 times greater than the affinity for chloride.

51. A molecularly imprinted polymer of example 47, wherein the affinity for acetate is 25 to 50 times greater than the affinity for chloride.

52. A molecularly imprinted polymer of example 47, wherein the affinity for acetate is 50 to 100 times greater than the affinity for chloride.

53. A molecularly imprinted polymer of example 47, wherein the affinity for acetate is 75 to 100 times greater than the affinity for chloride.

54. A molecularly imprinted polymer according to any one of embodiments 1 to 53, having an affinity for acetate that is greater than that of an organic molecule having covalently bound acetate or acetate groups, optionally wherein the organic molecule is 2-methyl-4-chlorophenoxyacetic acid, 2, 4-dichlorophenoxyacetic acid, 2,4, 5-trichlorophenoxyacetic acid, cortisone acetate, dexamethasone acetate, hydrocortisone acetate, betamethasone acetate 21, or phenoxyacetic acid.

55. The molecularly imprinted polymer of example 54, wherein the affinity for acetate is 10 to 100 times that for the organic molecule.

56. A molecularly imprinted polymer of example 55, wherein the affinity for acetate is 10 to 50 times greater than the affinity for the organic molecule.

57. A molecularly imprinted polymer of example 55, wherein the affinity for acetate is 10 to 20 times greater than the affinity for the organic molecule.

58. The molecularly imprinted polymer of example 55, wherein the affinity for acetate is 25 to 100 times greater than the affinity for the organic molecule.

59. The molecularly imprinted polymer of example 55, wherein the affinity for acetate is 25 to 50 times greater than the affinity for the organic molecule.

60. A molecularly imprinted polymer of embodiment 55, wherein the affinity for acetate is 50 to 100 times greater than the affinity for the organic molecule.

61. The molecularly imprinted polymer of example 55, wherein the affinity for acetate is 75 to 100 times greater than the affinity for the organic molecule.

62. The molecularly imprinted polymer of any one of embodiments 1 to 61, which is imprinted using a template in which acetate is the only organic moiety.

63. A molecularly imprinted polymer according to any one of embodiments 1 to 62, which is imprinted using a template having a molecular weight of not more than 200 g/mol.

64. A molecularly imprinted polymer of embodiment 63, which is imprinted using a template having a molecular weight of not more than 175 g/mol.

65. A molecularly imprinted polymer of embodiment 63, which is imprinted using a template having a molecular weight of not more than 150 g/mol.

66. A molecularly imprinted polymer of embodiment 63, which is imprinted using a template having a molecular weight of not more than 125 g/mol.

67. A molecularly imprinted polymer of embodiment 63, which is imprinted using a template having a molecular weight of not more than 100 g/mol.

68. The molecularly imprinted polymer of any one of embodiments 5 to 67, wherein the functional molecule and the second crosslinker, when present, correspond to at least 80% of the molecularly imprinted polymer dry weight.

69. A molecularly imprinted polymer of embodiment 68, wherein the functional molecule and the second crosslinker, when present, correspond to at least 85% of the molecularly imprinted polymer dry weight.

70. A molecularly imprinted polymer of embodiment 68, wherein the functional molecule and the second crosslinking agent, when present, correspond to at least 90% of the molecularly imprinted polymer dry weight.

71. A molecularly imprinted polymer of embodiment 68, wherein the functional molecule and the second crosslinking agent, when present, correspond to at least 95% of the molecularly imprinted polymer dry weight.

72. A molecularly imprinted polymer of embodiment 68, wherein the functional molecule and the second crosslinking agent, when present, correspond to at least 97% of the molecularly imprinted polymer dry weight.

73. A molecularly imprinted polymer of embodiment 68, wherein the functional molecule and the second crosslinking agent, when present, correspond to at least 99% of the molecularly imprinted polymer dry weight.

74. A molecularly imprinted polymer comprising one or more functional molecules, wherein at least 80 mol% of the functional molecules are functional cross-linkers.

75. A molecularly imprinted polymer of embodiment 74, wherein at least 85 mol% of the functional molecules are functional cross-linkers.

76. A molecularly imprinted polymer of embodiment 74, wherein at least 90 mol% of the functional molecules are functional cross-linkers.

77. A molecularly imprinted polymer of embodiment 74, wherein at least 95 mol% of the functional molecules are functional cross-linkers.

78. A molecularly imprinted polymer of embodiment 74, wherein at least 97 mol% of the functional molecules are functional cross-linkers.

79. A molecularly imprinted polymer of embodiment 74, wherein at least 99 mol% of the functional molecules are functional cross-linkers.

80. The molecularly imprinted polymer of embodiment 74, wherein the functional molecule consists essentially of or consists of a functional cross-linking agent.

81. The molecularly imprinted polymer of any one of embodiments 74 to 80, wherein the one or more functional molecules have been polymerized and crosslinked.

82. The molecularly imprinted polymer of any one of embodiments 74 to 81, wherein the one or more functional crosslinkers comprise one or more amide containing crosslinkers.

83. An molecularly imprinted polymer of embodiment 82, wherein the one or more functional cross-linking agents comprises or comprises N, N' -methylenebis (acrylamide) (MBA).

84. The molecularly imprinted polymer of any one of embodiments 74 to 83, wherein the one or more functional cross-linkers comprise one or more urea-containing cross-linkers.

85. A molecularly imprinted polymer of embodiment 84, wherein the one or more functional cross-linking agents comprise or consist of 1, 3-bis (4-vinylphenyl) urea, 1, 3-bis (4 (allyloxy) phenyl) urea, 1, 3-diallylurea, or a combination thereof.

86. The molecularly imprinted polymer of any one of embodiments 74 to 85, comprising one or more functional molecules and one or more second crosslinkers.

87. A molecularly imprinted polymer of embodiment 86, wherein the one or more second crosslinking agents comprise or consist of Ethylene Glycol Dimethacrylate (EGDA), ethylene glycol diacrylate, 1, 2-diallyloxybenzene, divinylbenzene, 1, 3-diisopropenylbenzene, divinylsuccinic acid, 1, 3-divinyltetramethyldisiloxane, tri (ethylene glycol) divinyl ether, di (ethylene glycol) divinyl ether, trimethylolpropane trimethacrylate, pentaerythritol triacrylate, or combinations thereof.

88. A molecularly imprinted polymer of embodiment 87, wherein the one or more second cross-linking agents comprise or consist of EGDA.

89. The molecularly imprinted polymer of any one of embodiments 86 to 88, wherein the molar ratio of the functional crosslinker to the second crosslinker is 1:5 to 5: 1.

90. The molecularly imprinted polymer of any one of embodiments 74 to 89, wherein the functional molecule and the second crosslinker, when present, correspond to at least 80% of the molecularly imprinted polymer dry weight.

91. The molecularly imprinted polymer of embodiment 90, wherein the functional molecule and the second crosslinking agent, when present, correspond to at least 85% of the molecularly imprinted polymer dry weight.

92. The molecularly imprinted polymer of embodiment 90, wherein the functional molecule and the second crosslinking agent, when present, correspond to at least 90% of the molecularly imprinted polymer dry weight.

93. The molecularly imprinted polymer of embodiment 90, wherein the functional molecule and the second crosslinking agent, when present, correspond to at least 95% of the molecularly imprinted polymer dry weight.

94. The molecularly imprinted polymer of embodiment 90, wherein the functional molecule and the second crosslinking agent, when present, correspond to at least 97% of the molecularly imprinted polymer dry weight.

95. The molecularly imprinted polymer of embodiment 90, wherein the functional molecule and the second crosslinking agent, when present, correspond to at least 99% of the molecularly imprinted polymer dry weight.

96. The molecularly imprinted polymer of any one of embodiments 74 to 95, capable of binding a target molecule that is a metabolite from the gut microbiota.

97. The molecularly imprinted polymer of any one of embodiments 74 to 96, which is capable of binding a target molecule that is a toxin.

98. The molecularly imprinted polymer of any one of embodiments 74 to 97, capable of binding a target molecule of a short chain fatty acid, a bile acid, a vitamin, an enzyme cofactor, an amino acid derivative, or a peptide.

99. The molecularly imprinted polymer of example 98, which is capable of binding a target molecule of a short chain fatty acid.

100. The molecularly imprinted polymer of embodiment 99, which is capable of binding one or more of acetate, propionate and butyrate.

101. The molecularly imprinted polymer of example 100, which is capable of binding acetate.

102. A molecularly imprinted polymer according to embodiment 101, wherein the molecularly imprinted polymer has a binding capacity of at least 5mg acetate per g of molecularly imprinted polymer in water.

103. A molecularly imprinted polymer according to example 102, wherein the molecularly imprinted polymer has an acetate binding capacity of 5mg acetate per g molecularly imprinted polymer to 40mg acetate per g molecularly imprinted polymer in water.

104. The molecularly imprinted polymer of embodiment 102 or embodiment 103, wherein the molecularly imprinted polymer has a binding capacity of at least 10mg acetate per g of molecularly imprinted polymer in water.

105. The molecularly imprinted polymer of embodiment 102 or embodiment 103, wherein the molecularly imprinted polymer has a binding capacity of at least 20mg acetate per g of molecularly imprinted polymer in water.

106. The molecularly imprinted polymer of embodiment 102 or embodiment 103, wherein the molecularly imprinted polymer has a binding capacity of at least 30mg acetate per g of molecularly imprinted polymer in water.

107. The molecularly imprinted polymer of embodiment 102 or embodiment 103, wherein the molecularly imprinted polymer has a binding capacity of at least 35mg acetate per g of molecularly imprinted polymer in water.

108. The molecularly imprinted polymer of any one of embodiments 102 to 107, wherein the binding capacity is determined by ion chromatography.

109. A molecularly imprinted polymer of embodiment 108, wherein acetate binding capacity is determined by ion chromatography as described in section 3.

110. The molecularly imprinted polymer of any one of embodiments 102 to 109, having a greater affinity for acetate than chloride as determined by ion chromatography.

111. A molecularly imprinted polymer of example 110, having greater affinity for acetate than chloride as determined by ion chromatography as described in section 3.

112. The molecularly imprinted polymer of example 110 or example 111, wherein the affinity for acetate is 10 to 100 times greater than the affinity for chloride.

113. A molecularly imprinted polymer of embodiment 112, wherein the affinity for acetate is 10 to 50 times greater than the affinity for chloride.

114. A molecularly imprinted polymer of embodiment 112, wherein the affinity for acetate is 10 to 20 times greater than the affinity for chloride.

115. A molecularly imprinted polymer of embodiment 112, wherein the affinity for acetate is 25 to 100 times greater than the affinity for chloride.

116. A molecularly imprinted polymer of embodiment 112, wherein the affinity for acetate is 25 to 50 times greater than the affinity for chloride.

117. A molecularly imprinted polymer of embodiment 112, wherein the affinity for acetate is 50 to 100 times greater than the affinity for chloride.

118. A molecularly imprinted polymer of embodiment 112, wherein the affinity for acetate is 75 to 100 times greater than the affinity for chloride.

119. A molecularly imprinted polymer according to any one of embodiments 102 to 118, having a greater affinity for acetate than an organic molecule having covalently bound acetate or acetate groups, optionally wherein the organic molecule is 2-methyl-4-chlorophenoxyacetic acid, 2, 4-dichlorophenoxyacetic acid, 2,4, 5-trichlorophenoxyacetic acid, cortisone acetate, dexamethasone acetate, hydrocortisone acetate, betamethasone acetate 21, or phenoxyacetic acid.

120. A molecularly imprinted polymer of example 119, wherein the affinity for acetate is 10 to 100 times greater than the affinity for the organic molecule.

121. A molecularly imprinted polymer of embodiment 120, wherein the affinity for acetate is 10 to 50 times greater than the affinity for organic molecules.

122. A molecularly imprinted polymer of embodiment 120, wherein the affinity for acetate is 10 to 20 times greater than the affinity for organic molecules.

123. A molecularly imprinted polymer of embodiment 120, wherein the affinity for acetate is 25 to 100 times greater than the affinity for the organic molecule.

124. A molecularly imprinted polymer of embodiment 120, wherein the affinity for acetate is 25 to 50 times greater than the affinity for organic molecules.

125. A molecularly imprinted polymer of embodiment 120, wherein the affinity for acetate is 50 to 100 times greater than the affinity for the organic molecule.

126. A molecularly imprinted polymer of embodiment 120, wherein the affinity for acetate is 75 to 100 times greater than the affinity for organic molecules.

127. A formulation comprising a population of molecularly imprinted polymer particles according to any one of embodiments 1 to 126. 128. The formulation of embodiment 127, wherein the molecularly imprinted polymer particles in the formulation have a D (v,0.5) particle size of from 10 μm to 50 μm.

129. The preparation of embodiment 127, wherein the molecularly imprinted polymer particles in the formulation have a D (v,0.5) particle size of from 10 μm to 40 μm.

130. The preparation of embodiment 127, wherein the molecularly imprinted polymer particles in the formulation have a D (v,0.5) particle size of from 10 μm to 30 μm.

131. The preparation of embodiment 127, wherein the molecularly imprinted polymer particles in the formulation have a D (v,0.5) particle size of from 10 μm to 20 μm.

132. The preparation of embodiment 127, wherein the molecularly imprinted polymer particles in the formulation have a D (v,0.5) particle size of from 15 μm to 50 μm.

133. The preparation of embodiment 127, wherein the molecularly imprinted polymer particles in the formulation have a D (v,0.5) particle size of from 15 μm to 40 μm.

134. The preparation of embodiment 127, wherein the molecularly imprinted polymer particles in the formulation have a D (v,0.5) particle size of from 15 μm to 30 μm.

135. The preparation of embodiment 127, wherein the molecularly imprinted polymer particles in the formulation have a D (v,0.5) particle size of from 15 μm to 25 μm.

136. The preparation of embodiment 127, wherein the molecularly imprinted polymer particles in the formulation have a D (v,0.5) particle size of from 15 μm to 20 μm.

137. The preparation of embodiment 127, wherein the molecularly imprinted polymer particles in the formulation have a D (v,0.5) particle size of from 20 μm to 50 μm.

138. The preparation of embodiment 127, wherein the molecularly imprinted polymer particles in the formulation have a D (v,0.5) particle size of from 20 μm to 40 μm.

139. The preparation of embodiment 127, wherein the molecularly imprinted polymer particles in the formulation have a D (v,0.5) particle size of from 20 μm to 30 μm.

140. The preparation of embodiment 127, wherein the molecularly imprinted polymer particles in the formulation have a D (v,0.5) particle size of from 30 μm to 50 μm.

141. The preparation of embodiment 127, wherein the molecularly imprinted polymer particles in the formulation have a D (v,0.5) particle size of from 30 μm to 40 μm.

142. The preparation of embodiment 127, wherein the molecularly imprinted polymer particles in the formulation have a D (v,0.5) particle size of from 40 μm to 50 μm.

143. The formulation of any one of embodiments 127 to 142, wherein the D (v,0.5) particle size is measured by a laser particle size analyzer.

144. The formulation of any one of embodiments 127 to 142, wherein the formulation is at least 85% pure.

145. The formulation of embodiment 144, wherein the formulation is 85% to 99% pure.

146. The formulation of embodiment 144, wherein the formulation is 85% to 99% pure or more.

147. The formulation of embodiment 144, wherein the formulation is 85% to 99.5% pure or more.

148. The formulation of embodiment 144, wherein the formulation is 85% to 99.8% pure or greater.

149. The formulation of any one of embodiments 144 to 148, wherein the formulation is at least 90% pure.

150. The formulation of any one of embodiments 144 to 148, wherein the formulation is at least 95% pure.

151. The formulation of any one of embodiments 144 to 148, wherein the formulation is at least 96% pure.

152. The formulation of any one of embodiments 144 to 148, wherein the formulation is at least 97% pure.

153. The formulation of any one of embodiments 144 to 148, wherein the formulation is at least 98% pure.

154. The formulation of any one of embodiments 144 to 148, wherein the formulation is at least 99% pure.

155. The formulation of any one of embodiments 144 to 154, wherein the purity is purity determined by infrared spectroscopy.

156. A method for making the molecularly imprinted polymer of any one of embodiments 5 to 73, comprising polymerizing and crosslinking a mixture comprising one or more functional molecules and one or more template molecules.

157. The method of embodiment 156, wherein the molar ratio of the one or more functional molecules to the one or more template molecules is from 1:1 to 15: 1.

158. The method of embodiment 157, wherein the molar ratio of the one or more functional molecules to the one or more template molecules is from 1:1 to 5: 1.

159. The method of embodiment 158, wherein the molar ratio of the one or more functional molecules to the one or more template molecules is 3:1 to 4: 1.

160. The method of embodiment 159, wherein the molar ratio of the one or more functional molecules to the one or more template molecules is 3: 1.

161. The method of embodiment 159, wherein the molar ratio of the one or more functional molecules to the one or more template molecules is 4: 1.

162. A method for making the molecularly imprinted polymer of any one of embodiments 74 to 126, comprising polymerizing and crosslinking a mixture comprising one or more functional molecules and one or more template molecules.

163. The method of embodiment 162, wherein the molar ratio of the one or more functional crosslinkers to the one or more template molecules is from 1:1 to 15: 1.

164. The method of embodiment 163, wherein the molar ratio of the one or more functional molecules to the one or more template molecules is from 1:1 to 5: 1.

165. The method of embodiment 164, wherein the molar ratio of the one or more functional molecules to the one or more template molecules is 3:1 to 4: 1.

166. The method of embodiment 165, wherein the molar ratio of the one or more functional molecules to the one or more template molecules is 3: 1.

167. The method of embodiment 165, wherein the molar ratio of the one or more functional molecules to the one or more template molecules is 4: 1.

168. The process of any one of embodiments 162 to 167, wherein the one or more template molecules comprise one or more target molecules and/or one or more salts thereof.

169. A method for making the molecularly imprinted polymer of any one of embodiments 101 to 126, comprising polymerizing and crosslinking a mixture comprising one or more functional molecules and one or more template molecules.

170. The method of embodiment 169, wherein the molar ratio of the one or more functional crosslinkers to the one or more template molecules is 1:1 to 15: 1.

171. The method of embodiment 170, wherein the molar ratio of the one or more functional molecules to the one or more template molecules is from 1:1 to 5: 1.

172. The method of embodiment 171, wherein the molar ratio of the one or more functional molecules to the one or more template molecules is 3:1 to 4: 1.

173. The method of embodiment 171, wherein the molar ratio of the one or more functional molecules to the one or more template molecules is 3: 1.

174. The method of embodiment 171, wherein the molar ratio of the one or more functional molecules to the one or more template molecules is 4: 1.

175. The process of any one of embodiments 144-161 or 169-174, wherein the one or more template molecules comprise one or more short chain fatty acids and/or one or more salts thereof.

176. Example 144-161 or 169-174, wherein the one or more template molecules comprise acetate and/or one or more salts thereof, propionate and/or one or more salts thereof, isobutyrate and/or one or more salts thereof, butyrate and/or one or more salts thereof, pivalate and/or one or more salts thereof, benzoate and/or one or more salts thereof, malonate and/or one or more salts thereof, succinate and/or one or more salts thereof, bicarbonate and/or one or more salts thereof, or carbonate and/or one or more salts thereof.

177. The method of embodiment 176, wherein the one or more template molecules comprise acetate and/or one or more salts thereof.

178. The method of embodiment 177, wherein the one or more template molecules comprise acetate.

179. The method of embodiment 178, wherein the acetate salt comprises potassium acetate and/or sodium acetate.

180. The method of embodiment 179, wherein the acetate salt is potassium acetate.

181. The method of embodiment 179, wherein the acetate salt is sodium acetate.

182. The method of any one of embodiments 176 to 181, wherein acetate is the only organic moiety in the one or more template molecules.

183. The method of any one of embodiments 176 to 182, wherein the one or more template molecules have a molecular weight of no more than 200 g/mol.

184. The method of embodiment 183, wherein the one or more template molecules have a molecular weight of no more than 175 g/mol.

185. The method of embodiment 183, wherein the one or more template molecules have a molecular weight of no more than 150 g/mol.

186. The method of embodiment 183, wherein the one or more template molecules have a molecular weight of no more than 125 g/mol.

187. The method of embodiment 183, wherein the one or more template molecules have a molecular weight of no more than 100 g/mol.

188. The method of embodiment 176, wherein the one or more template molecules comprise propionate and/or one or more salts thereof.

189. The method of embodiment 176, wherein the one or more template molecules comprise isobutyrate and/or one or more salts thereof.

190. The method of embodiment 176, wherein the one or more template molecules comprise butyrate and/or one or more salts thereof.

191. The method of embodiment 176, wherein the one or more template molecules comprise pivalate and/or one or more salts thereof.

192. The method of embodiment 176, wherein the one or more template molecules comprise benzoate and/or one or more salts thereof.

193. The method of embodiment 176, wherein the one or more template molecules comprise malonic acid and/or one or more salts thereof.

194. The method of embodiment 176, wherein the one or more template molecules comprise succinate and/or one or more salts thereof.

195. The method of embodiment 176, wherein the one or more template molecules comprise bicarbonate and/or one or more salts thereof.

196. The method of embodiment 176, wherein the one or more template molecules comprise a carbonate salt and/or one or more salts thereof.

197. When dependent directly or indirectly on example 19 or example 86, the process of any one of examples 144 to 196, wherein the mixture further comprises one or more secondary crosslinkers.

198. The process of any one of embodiments 144 to 197, wherein the mixture comprises one or more solvents.

199. The method of embodiment 198, wherein the one or more solvents comprise methanol (MeOH).

200. The process of any one of embodiments 144 to 199, further comprising forming a mixture.

201. The process of any one of embodiments 144 to 200, further comprising degassing the mixture prior to polymerizing.

202. The process of example 201, wherein degassing comprises bubbling an inert gas through the mixture.

203. The process of example 202 wherein the gas is nitrogen or argon.

204. The process of any of embodiments 201 to 203, wherein the temperature of the mixture during degassing is 60 ℃ to 80 ℃.

205. The process of any of embodiments 144 to 204, wherein the temperature of the mixture during polymerization is from 60 ℃ to 80 v.

206. The process of any one of embodiments 144 to 197, wherein the polymerization is initiated by an initiator.

207. The process of embodiment 206, wherein the initiator comprises a photoinitiator or a thermal initiator.

208. The process of embodiment 207, wherein the initiator comprises potassium persulfate, sodium persulfate, ammonium persulfate, dimethyl azobisisobutyrate (V601), Azobisisobutyronitrile (AIBN), benzoyl peroxide, t-butyl hydroperoxide, acetyl peroxide, 2-hydroxy-4' - (2-hydroxyethoxy) -2 methylpropanol, or a combination thereof.

209. The method of embodiment 208, wherein the initiator comprises ammonium persulfate.

210. The process of any one of embodiments 144 to 209, further comprising washing the molecularly imprinted polymer to remove the one or more template molecules.

211. The method of embodiment 210, wherein the washing comprises washing the molecularly imprinted polymer with one or more solvents.

212. The method of embodiment 211, comprising washing the molecularly imprinted polymer with more than one solvent sequentially.

213. The method of embodiment 212, comprising washing the molecularly imprinted polymer with methanol, water, and ethanol sequentially.

214. The process of any one of embodiments 211 to 213, wherein said washing comprises performing a soxhlet extraction.

215. The process of any one of embodiments 144 to 214, further comprising drying the molecularly imprinted polymer.

216. The process of any one of embodiments 144 to 215, further comprising comminuting or grinding the molecularly imprinted polymer.

217. The process of any one of embodiments 144 to 216, further comprising selecting molecularly imprinted polymer particles having a desired size.

218. The process of embodiment 217, wherein selecting molecularly imprinted polymer particles having a desired size comprises filtering the molecularly imprinted polymer through one or more sieves.

219. The process of embodiment 218, wherein the one or more screens comprise a 300 mesh screen, a 500 mesh screen, a 900 mesh screen, an 1800 mesh screen, or a combination thereof.

220. The process of embodiment 219, wherein the one or more screens comprise a 300 mesh screen, a 500 mesh screen, a 900 mesh screen, and an 1800 mesh screen.

221. The process of any one of embodiments 217 to 219, comprising selecting molecularly imprinted polymer particles having a D (v,0.5) particle size of 50 μm or less.

222. The method of embodiment 221, comprising selecting molecularly imprinted polymer particles having a D (v,0.5) particle size of from 10 μm to 50 μm.

223. The method of embodiment 222, comprising selecting molecularly imprinted polymer particles having a D (v,0.5) particle size of from 10 μm to 40 μm.

224. The method of embodiment 222, comprising selecting molecularly imprinted polymer particles having a D (v,0.5) particle size of from 10 μm to 30 μm.

225. The method of embodiment 222, comprising selecting molecularly imprinted polymer particles having a D (v,0.5) particle size of from 10 μm to 20 μm.

226. The method of embodiment 222, comprising selecting molecularly imprinted polymer particles having a D (v,0.5) particle size of from 15 μm to 50 μm.

227. The method of embodiment 222, comprising selecting molecularly imprinted polymer particles having a D (v,0.5) particle size of from 15 μm to 40 μm.

228. The method of embodiment 222, comprising selecting molecularly imprinted polymer particles having a D (v,0.5) particle size of from 15 μm to 30 μm.

229. The method of embodiment 222, comprising selecting molecularly imprinted polymer particles having a D (v,0.5) particle size of from 15 μm to 25 μm.

230. The method of embodiment 222, comprising selecting molecularly imprinted polymer particles having a D (v,0.5) particle size of from 15 μm to 20 μm.

231. The method of embodiment 222, comprising selecting molecularly imprinted polymer particles having a D (v,0.5) particle size of from 20 μm to 50 μm.

232. The method of embodiment 222, comprising selecting molecularly imprinted polymer particles having a D (v,0.5) particle size of from 20 μm to 40 μm.

233. The method of embodiment 222, comprising selecting molecularly imprinted polymer particles having a D (v,0.5) particle size of from 20 μm to 30 μm.

234. The method of embodiment 222, comprising selecting molecularly imprinted polymer particles having a D (v,0.5) particle size of from 30 μm to 50 μm.

235. The method of embodiment 222, comprising selecting molecularly imprinted polymer particles having a D (v,0.5) particle size of from 30 μm to 40 μm.

236. The method of embodiment 222, comprising selecting molecularly imprinted polymer particles having a D (v,0.5) particle size of from 40 μm to 50 μm.

237. The process of any one of embodiments 221 to 236, wherein the D (v,0.5) particle size is measured by a laser particle size analyzer.

238. A molecularly imprinted polymer produced by the method of any one of examples 156 to 237.

239. A formulation comprising a population of molecularly imprinted polymer particles produced by the treatment of any one of embodiments 156-237.

240. A pharmaceutical composition comprising (i) a molecularly imprinted polymer of any one of embodiments 1 to 126 or 238 or a formulation of any one of embodiments 127 to 155 or 239 and (ii) a pharmacologically acceptable excipient.

241. The pharmaceutical composition of embodiment 240 formulated for oral use.

242. The pharmaceutical composition of embodiment 241, which is a liquid.

243. The pharmaceutical composition of embodiment 242, which is a suspension.

244. The pharmaceutical composition of embodiment 242, which is a solution.

245. The pharmaceutical composition of any one of embodiments 242-244, wherein the excipient comprises water, saline, ethanol, propylene glycol, 1,3 butylene glycol, oil, glycerol, polyethylene glycol, or any combination thereof.

246. The pharmaceutical composition of embodiment 241, which is a solid.

247. The pharmaceutical composition of embodiment 246, wherein the excipient comprises one or more of starch, lactose, dextrose, sucrose, glucose, mannitol, silicic acid, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, acacia, agar, calcium carbonate, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a combination of any of the foregoing.

248. The pharmaceutical composition of embodiment 246 or embodiment 247, which is a capsule.

249. The pharmaceutical composition of embodiment 246 or embodiment 247, which is a tablet.

250. The pharmaceutical composition of embodiment 246 or embodiment 247, which is a powder.

251. The pharmaceutical composition of embodiment 246 or embodiment 247, which is a granule.

252. The pharmaceutical composition of embodiment 246 or embodiment 247, which is an oral tablet.

253. The pharmaceutical composition of embodiment 246 or embodiment 247, which is a chewing gum.

254. The pharmaceutical composition of embodiment 246 or embodiment 247, which is a buccal tablet.

255. A method of sequestering acetate in the gastrointestinal tract of a subject, comprising orally administering to the subject an effective amount of a molecularly imprinted polymer capable of binding acetate.

256. A method of treating a subject diagnosed with or at risk of a condition associated with acetate accumulation comprising administering to the subject an effective amount of a molecularly imprinted polymer capable of binding acetate.

257. The method of embodiment 256, wherein the condition associated with acetate accumulation comprises metabolic syndrome.

258. The method of embodiment 256, wherein the condition associated with acetate accumulation comprises obesity.

259. A method of reducing body weight in a subject, comprising orally administering to the subject an effective amount of a molecularly imprinted polymer capable of binding acetate.

260. The method of any one of embodiments 255 to 259, comprising administering to a subject an acetate-binding molecularly imprinted polymer according to any one of embodiments 1 to 126 or 238, the preparation according to any one of embodiments 127 to 155 or 239, or the pharmaceutical composition (or solution or suspension made from the pharmaceutical composition) according to any one of embodiments 240 to 254, comprising the acetate-binding molecularly imprinted polymer.

261. A method of sequestering a target molecule in the gastrointestinal tract of a subject, comprising administering to the subject an effective amount of a molecularly imprinted polymer binding to the target molecule according to any one of examples 1 to 126 or 238, a formulation comprising a molecularly imprinted polymer binding to the target molecule according to any one of examples 127 to 155 or 239, or a pharmaceutical composition (or a solution or suspension made from a pharmaceutical composition) comprising a molecularly imprinted polymer binding to the target molecule according to any one of examples 240 to 254.

262. A method of treating a subject diagnosed with or at risk of a condition associated with accumulation of a target molecule, comprising administering to the subject an effective amount of the molecularly imprinted polymer of any one of examples 1 to 126 or 238 that binds to the target molecule, a formulation of any one of examples 127 to 155 or 239 comprising a molecularly imprinted polymer that binds to the target molecule, or a pharmaceutical composition (or solution or suspension made from a pharmaceutical composition) according to any one of examples 240 to 254 comprising a molecularly imprinted polymer that binds to the target molecule.

263. The method of any one of embodiments 255 to 262, wherein the molecularly imprinted polymer, formulation or pharmaceutical composition (or a solution or suspension made from the pharmaceutical composition) is administered orally.

264. The method of any one of embodiments 255 to 263, comprising administering the molecularly imprinted polymer mixed with food.

265. The method of any one of embodiments 255 to 264, wherein 100mg to 500g of the molecularly imprinted polymer is administered to the subject per day.

266. The method of embodiment 265, wherein the subject is administered 100mg to 1g of the molecularly imprinted polymer per day.

267. The method of embodiment 265, wherein the subject is administered 1g to 5g of the molecularly imprinted polymer per day.

268. The method of embodiment 265, wherein the subject is administered 1g to 10g of the molecularly imprinted polymer per day.

269. The method of embodiment 265, wherein the subject is administered 5g to 15g of the molecularly imprinted polymer per day.

270. The method of embodiment 265, wherein the subject is administered 10g to 25g of the molecularly imprinted polymer per day.

271. The method of embodiment 265, wherein the subject is administered 20g to 50g of the molecularly imprinted polymer per day.

272. The method of embodiment 265, wherein the subject is administered 20g to 100g of the molecularly imprinted polymer per day.

273. The method of embodiment 265, wherein the subject is administered 50g to 100g of the molecularly imprinted polymer per day.

274. The method of embodiment 265, wherein the subject is administered 50g to 200g of the molecularly imprinted polymer per day.

275. The method of embodiment 265, wherein the subject is administered 100g to 200g of the molecularly imprinted polymer per day.

276. The method of embodiment 265, wherein the subject is administered 100g to 500g of the molecularly imprinted polymer per day.

277. The method of embodiment 265, wherein the subject is administered 200g to 500g of the molecularly imprinted polymer per day.

278. The method of embodiment 265, wherein the subject is administered 300g to 500g of the molecularly imprinted polymer per day.

All publications, patents, patent applications, and other documents cited in this application are incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent application, or other document were individually indicated to be incorporated by reference for all purposes. If there is an inconsistency between the teachings of one or more of the references contained herein and the present disclosure, the teachings of the present specification are intended to be used.

Claims

1. A molecularly imprinted polymer capable of binding acetate, the molecularly imprinted polymer comprising:

one or more functional molecules comprising N, N '-methylenebis (acrylamide) and ethylene glycol dimethacrylate, wherein the molar ratio of the N, N' -methylenebis (acrylamide) to the ethylene glycol dimethacrylate is 1:1 to 4: 5.

2. A molecularly imprinted polymer according to claim 1, wherein the molecularly imprinted polymer is capable of binding acetate in the human gastrointestinal tract.

3. A molecularly imprinted polymer according to claim 1, wherein at least 90 mol% of the functional molecules in the molecularly imprinted polymer are functional cross-linking agents.

4. A molecularly imprinted polymer according to claim 1, wherein at least 95% mol of the functional molecules in the molecularly imprinted polymer are functional cross-linking agents.

5. A molecularly imprinted polymer according to claim 1, wherein at least 97% mol of the functional molecules in the molecularly imprinted polymer are functional cross-linking agents.

6. A molecularly imprinted polymer according to claim 1, wherein at least 99% mol of the functional molecules in said molecularly imprinted polymer are functional cross-linking agents.

7. A molecularly imprinted polymer as claimed in any one of claims 1 to 6, wherein the molecularly imprinted polymer has an acetate binding capacity in water ranging from 5g acetate to 40g acetate per g molecularly imprinted polymer.

8. The molecularly imprinted polymer as claimed in claim 7, wherein the molecularly imprinted polymer has an acetate binding capacity in water ranging from 20g to 40g acetate per g molecularly imprinted polymer.

9. The molecularly imprinted polymer of claims 1-8, wherein the molecularly imprinted polymer has a greater affinity for acetate than chloride.

10. The molecularly imprinted polymer of claims 1-8, wherein the molecularly imprinted polymer has a D (v,0.5) particle size of 10 μm to 50 μm.

11. The molecularly imprinted polymer according to claim 10, wherein the molecularly imprinted polymer has a D (v,0.5) particle size of 10 μ ι η to 40 μ ι η.

12. The molecularly imprinted polymer according to claim 10, wherein the molecularly imprinted polymer has a D (v,0.5) particle size of 15 μ ι η to 25 μ ι η.

13. The molecularly imprinted polymer according to claims 1 to 12, wherein the molar ratio of N, N' -methylenebis (acrylamide) is always 1:1.

14. A molecularly imprinted polymer according to claims 1 to 12, wherein the molecularly imprinted polymer comprises polymerizing and crosslinking with the N, N' -methylenebis (acrylamide) and the ethylene glycol dimethacrylate in the presence of one or more template molecules comprising acetate and/or a salt thereof.

15. A molecularly imprinted polymer according to claim 14, wherein the one or more template molecules comprise potassium acetate.

16. A pharmaceutical composition comprising a molecularly imprinted polymer according to any one of claims 1 to 15 and pharmaceutically acceptable excipients thereof.

17. Use of a molecularly imprinted polymer according to any one of claims 1-15 for the preparation of a pharmaceutical composition for the treatment of a subject diagnosed with or at risk of a condition associated with acetate accumulation.

18. A method of preparing a pharmaceutical composition comprising a molecularly imprinted polymer capable of binding acetate, the method comprising polymerizing and crosslinking N, N '-methylenebis (acrylamide) and ethylene glycol dimethacrylate in the presence of one or more template molecules, wherein the molar ratio of N, N' -methylenebis (acrylamide) to ethylene glycol dimethacrylate is from 1:1 to 4:5, wherein the one or more template molecules comprise acetate and/or a salt thereof.

19. A method as claimed in claim 18 wherein said one or more template molecules comprise acetate.

20. A process as claimed in claim 19 wherein said acetate salt comprises potassium acetate and/or sodium acetate.

21. A process as claimed in claim 19 wherein the acetate salt is potassium acetate.

22. A pharmaceutical composition, comprising:

a molecularly imprinted polymer capable of binding acetate and pharmaceutically acceptable excipients thereof,

the molecularly imprinted polymer comprises one or more functional molecules, wherein the functional molecules comprise N, N '-methylene bis (acrylamide) and ethylene glycol dimethacrylate, and the molar ratio of the N, N' -methylene bis (acrylamide) to the ethylene glycol dimethacrylate is 1:1 to 4: 5.

23. The pharmaceutical composition of claim 22, wherein the molecularly imprinted polymer is capable of binding acetate in the human gastrointestinal tract.

24. The pharmaceutical composition of claim 22, wherein at least 80% mol of the functional molecules in the molecularly imprinted polymer are functional cross-linkers.

25. The pharmaceutical composition of claim 22, wherein the molecularly imprinted polymer has an acetate binding capacity in water ranging from 5g acetate to 40g acetate per g molecularly imprinted polymer.

26. The pharmaceutical composition of claim 25, wherein the molecularly imprinted polymer has an acetate binding capacity in water ranging from 20g acetate to 40g acetate per g molecularly imprinted polymer.

27. The pharmaceutical composition of claim 22, wherein the molecularly imprinted polymer has a greater affinity for acetate than chloride.

28. The pharmaceutical composition of claim 22, wherein the molecularly imprinted polymer has a particle size D (v,0.5) of 10 μ ι η to 50 μ ι η.

29. The pharmaceutical composition of claim 28, wherein the molecularly imprinted polymer has a particle size D (v,0.5) of 10 μ ι η to 40 μ ι η.

30. The pharmaceutical composition of claim 28, wherein the molecularly imprinted polymer has a particle size D (v,0.5) of 15 μ ι η to 25 μ ι η.

31. The pharmaceutical composition as claimed in claim 22, wherein the N, N' -methylenebis (acrylamide) is always in a molar ratio of 1:1 with respect to the ethylene glycol dimethacrylate.

32. The pharmaceutical composition of claim 31, wherein the molecularly imprinted polymer has a greater affinity for acetate than chloride.

33. Use of the pharmaceutical composition of claim 22 in the preparation of a medicament for treating acetate in the gastrointestinal tract of a sequestered subject.

34. Use of the pharmaceutical composition of claim 22 in the preparation of a medicament for treating weight loss in a subject.

35. Use of the pharmaceutical composition of claim 22 in the preparation of a medicament for treating a condition associated with acetate accumulation, including metabolic syndrome.

36. Use of the pharmaceutical composition of claim 22 in the manufacture of a medicament for the treatment of conditions associated with acetate accumulation, including obesity.