CN114377139B - Carrier, drug delivery system and application thereof - Google Patents
Carrier, drug delivery system and application thereof Download PDFInfo
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- CN114377139B CN114377139B CN202210241151.0A CN202210241151A CN114377139B CN 114377139 B CN114377139 B CN 114377139B CN 202210241151 A CN202210241151 A CN 202210241151A CN 114377139 B CN114377139 B CN 114377139B
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- carrier
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- dermatan sulfate
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Images
Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a carrier, a drug delivery system and application thereof. The carrier provided by the application comprises: dermatan sulfate and thioketal compound connected with dermatan sulfate, the structure of the thioketal compound is shown as formula (I), R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 And R is 8 Each independently selected from hydrogen, C 1‑10 At least one of alkyl, hydroxy, amino, carboxyl, halogen, R 9 And R is 10 And X and Y are each independently selected from at least one of carboxyl, hydroxyl, amino, acyl halide and isocyanate groups. The carrier has good specificity and excellent Reactive Oxygen Species (ROS) response activity in the aspect of targeting melanoma, is beneficial to enhancing anti-tumor immune response, can be self-assembled with a plurality of hydrophobic drugs to construct a bionic nano-chemical immunotherapy drug, effectively improves drug loading capacity,thus constructing a nano target therapy system responding to the tumor microenvironment.
Description
Technical Field
The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a carrier, a drug delivery system and application thereof.
Background
Melanoma is a tumor from malignant skin melanocyte, and has high malignant degree, and immunotherapy is the most promising therapeutic means after operation and radiotherapy and chemotherapy. Whereas melanoma maintains an immunosuppressive microenvironment by secreting immunosuppressive cytokines and by a tolerant death pathway, the non-immunogenicity of tumor cells results in a low response rate and poor efficacy of immunotherapy. By different induction methods, the non-immunogenicity of tumor cells can be converted into immunogenicity, mediating anti-tumor immune responses, thereby killing tumor cells, a phenomenon known as immunogenic cell death (Immunogenic cell death, ICD). ICD can induce damage-associated molecular patterns (DAMPs) leading to up-regulation of Calreticulin (CRT), release of heat shock proteins (HSP 70 and HSP 90), high mobility group protein B1 (HMGB 1) and ATP, which signals induce cytotoxic T lymphocytes (CD) by stimulating recruitment maturation and antigen presentation of Dendritic Cells (DCs) 8+ CTLs) to activate the host's immune system, thereby inhibiting the tumor.
ICD-based immunotherapy has been less responsive and prone to safety problems in the past decade, despite some progress, such as induction of ICD development with radiotherapy, photodynamic therapy and pathogens, resulting in the fact that most of the developed therapies have not been shifted from laboratory studies to clinical applications. In fact, anthraquinone drugs, represented by Doxorubicin (DOX), have proven to be a class of good ICD inducers, also known as Chemoimmunotherapy (Chemoimmunotherapy). However, effective concentrations of ICD inducers often accompany dose-dependent toxic side effects such as myocardial damage in use. Although the development of advanced drug delivery systems can achieve "attenuation synergy" for drugs to some extent, existing "target-ligand" based drug delivery systems often have insufficient specificity resulting in high off-target effects due to the lack of specific markers for melanoma cells. In recent years, bionic drug delivery systems based on in vivo cells or endogenous substances and the like simulate in vivo delivery processes, and the efficiency and accuracy of delivery are greatly improved. Therefore, constructing a biomimetic melanoma targeted drug delivery system is an effective approach.
Disclosure of Invention
The application aims to provide a carrier and a drug delivery system, so that the bionic melanoma targeted drug delivery system is constructed to be applied to chemotherapy, and melanoma is effectively inhibited.
In order to achieve the above purpose, the specific technical scheme provided by the application is as follows:
in a first aspect, the present application provides a vector comprising: dermatan sulfate and a thioketal compound connected with the dermatan sulfate, wherein the structure of the thioketal compound is shown as a formula (I):
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 And R is 8 Each independently selected from hydrogen, C 1-10 At least one of alkyl, hydroxy, amino, carboxyl, halogen, R 9 And R is 10 And X and Y are each independently selected from at least one of carboxyl, hydroxyl, amino, acyl halide and isocyanate groups.
The carrier mainly comprises dermatan sulfate and thioketal compounds, the dermatan sulfate has excellent bionic homing targeting on melanoma, the thioketal compounds have good specificity on the aspect of targeting melanoma, the structure of the thioketal compounds is shown as a formula (I), and the thioketal compounds have excellent Reactive Oxygen Species (ROS) response activity, so that the thioketal compounds can be hydrolyzed at focus positions to realize drug release, and the dermatan sulfate is cooperated, so that the concentration of the drugs at the melanoma positions is favorably improved, the induction effect of the drugs on ICD is enhanced, the antitumor immune response is enhanced, the other organ side effects caused by the nonspecific distribution of the drugs are avoided, in addition, the thioketal compounds are adopted for functionally modifying dermatan sulfate, the problem that the dermatan sulfate cannot load hydrophobic drugs due to strong hydrophilicity is solved, meanwhile, the self-assembly of the carrier and a plurality of hydrophobic drugs provided by the application can be induced and promoted to construct bionic nano-chemotherapy drugs, the drug loading capacity is effectively improved, and a nano target system for responding to tumor microenvironment is constructed.
In some embodiments, the thioketal is linked to the dermatan sulfate with a chemical bond comprising at least one of an ester bond, an ether bond, an amide bond, and a carbonate bond.
In some embodiments, the thioketal is selected from any one of the following:
in some embodiments, 32-192 molecules of the thioketal compound are attached per molecule of the dermatan sulfate.
In some embodiments, the dermatan sulfate has a structure according to formula (ii):
wherein m and n represent the degree of polymerization, m+n=64, and m/n is not less than 1.
In a further embodiment, the amount of said thioketal compound attached per molecule of said dermatan is from 0.5 to 3 times the sum of m and n.
In some embodiments, the carrier is a nanosphere polymer; and/or
The particle size of the carrier is 30-900nm.
In a second aspect, the present application provides a drug delivery system comprising: an effective dose of the drug molecules and a carrier for loading the drug molecules, wherein the carrier is the carrier.
The drug delivery system provided by the application can be applied to chemotherapy of melanoma based on the carrier, has the characteristics of high immune response, low toxic and side effect, high drug loading capacity and stable system, can carry most of hydrophobic drugs, has a wide application range and has good market application prospect.
In some embodiments, the drug molecule is a hydrophobic anti-tumor drug selected from at least one of doxorubicin, epirubicin, daunorubicin, mitoxantrone, camptothecin, irinotecan; and/or
The drug delivery system is an injectable formulation.
In a third aspect, the present application provides the use of the aforementioned carrier or the aforementioned drug delivery system for the preparation of an anti-melanoma drug.
Experiments prove that the drug delivery system constructed by the carrier provided by the application has good activity of inhibiting the growth of melanoma at both a cell level and an animal level, and has application prospect of preparing anti-melanoma drugs.
Drawings
FIG. 1 is a diagram showing the nuclear magnetic resonance hydrogen spectra of ADS and UDS, wherein the upper diagram shows the nuclear magnetic resonance hydrogen spectrum of ADS, the lower diagram shows the nuclear magnetic resonance hydrogen spectrum of UDS, the chemical structural formulas of the upper diagram are marked with the numerals of a, b, c, d, e, f, 1 and 2, and the chemical structural formulas of the lower diagram are marked with the numerals of a, b, c, 1 and 2, so as to identify the hydrogen attribution on the hydrogen spectrum, the numeral proton signals of DS is translated into a DS hydrogen signal, and the horizontal coordinate is chemical displacement;
fig. 2 is a TEM image of ADS NP in PBS buffer and hydrogen peroxide, the left image corresponds to the PBS buffer, and the right image corresponds to the hydrogen peroxide;
FIG. 3 shows the particle size distribution of ADS NPs before and After the dispersion of ADS NPs in hydrogen peroxide (After 1mM H in After) 2 O 2 Exposure) particle size distribution, ADS NP (Before H) on the right 2 O 2 Exposure) dispersed in hydrogen peroxideThe previous particle size distribution;
FIG. 4 shows ADS NP at different H 2 O 2 Hydrolysis conditions in hydrogen peroxide with concentration, wherein the ordinate represents hydrolysis rate and the abscissa represents time;
FIG. 5 shows hydrolysis of ADS NP and UDS NP in different reactive oxygen species, wherein the ordinate indicates hydrolysis rate and the abscissa indicates different ROS environments, wherein each set of ROS environments corresponds to UDS NP on the left and ADS NP on the right;
FIG. 6 is a TEM image of DOX/ADS NPs and DOX/UDS NPs in PBS buffer;
FIG. 7 is a graph of DOX/ADS NP and DOX/UDS NP Drug Loading (DLC) and drug Encapsulation Efficiency (EE) test results, wherein the left side of each set of results corresponds to DOX/UDS NP and the right side corresponds to DOX/ADS NP;
FIG. 8 is an ultraviolet scan profile of DOX, DOX/ADS NP and DOX/UDS NP, with wavelength on the abscissa and absorbance on the ordinate;
FIG. 9 shows the relative particle size change of DOX/ADS NP in the presence of potassium chloride (KCl), urea (Urea), and Sodium Dodecyl Sulfate (SDS), with time on the abscissa and relative particle size on the ordinate;
FIG. 10 is a molecular docking simulation between DOS and ATK, wherein hydrophobic interaction (Alkyl) is the hydrophobic interaction between Alkyl groups, hydrogen bond is the hydrogen bond, hydrophobic interaction (pi-pi stacking) is the pi-pi stacking hydrophobic interaction, electrostatic interaction (pi-anion interaction) is the pi-anion electrostatic interaction, 3.6 and 3.9 are the pi-pi stacking plane distance between the fluorene ring of ATK and the aromatic ring of DOX, 3.0 is the glycoside bond to fluorene ring distance of DOX, 3.5 is the Alkyl carbon of ATK to the sugar unit of DOX, 2.0 is the carboxyl oxygen of ATK to the amino hydrogen of DOX in angstroms;
FIG. 11 shows the results of flow analysis of apoptosis of tumor cells corresponding to PBS, DOX, DOX/UDS NP and DOX/ADS NP, wherein A is a cell flow chart, B is a statistical result of cell proportion corresponding to the cell flow chart, and the ordinate is the proportion of apoptotic cells.
FIG. 12 shows tumor changes and weight changes of mice corresponding to PBS, DOX, DOX/UDS NP and DOX/ADS NP, wherein A shows tumor volume changes after administration, and the abscissa shows time and the ordinate shows tumor volume; b shows the tumor weight comparison after administration, and the ordinate is the tumor weight; c shows the concentration of the drug DOX in the tumor after the drug administration, the ordinate is the relative concentration of the drug DOX in the tumor, and the relative concentration of the DOX group is 1 as a standard; d shows the change in mouse body weight, and the ordinate is mouse body weight.
FIG. 13 shows CD80 in peritumor lymph node tissue of mice corresponding to PBS, DOX, DOX/UDS NP and DOX/ADS NP + CD86 + Wherein A is a cell flow chart, B is a cell proportion statistical result corresponding to the cell flow chart, and the ordinate is the proportion of the mature dendritic cells.
FIG. 14 is CD in spleen tissue of mice corresponding to PBS, DOX, DOX/UDS NP and DOX/ADS NP 3+ CD 4+ T cells and CD 3+ CD 8+ Flow analysis results of T cells, wherein A is a cell flow chart, B is a cell proportion statistical result corresponding to the cell flow chart, and the ordinate is CD respectively 3+ CD 4+ T cell duty cycle and CD 3+ CD 8+ T cell duty cycle.
Detailed Description
In the description of the present application, the compounds and derivatives thereof are named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstract service, in golomb, ohio) naming system, and the specific reference to the compound groups are set forth and described below:
"alkyl" refers to a class of saturated chain hydrocarbon radicals containing only two atoms, carbon and hydrogen, having straight and/or branched carbon chains, including but not limited to-CH 3 、-CH 2 -、-CH 2 CH 3 、-CH(CH 3 )-、-CH 2 CH 2 -、-CH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 -、-CH(CH 3 ) 2 、-C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH(CH 3 ) 2 、-CH 2 C(CH 3 ) 2 -、-CH(CH 3 )CH 2 CH 3 、-CH(CH 3 )CH 2 CH 3 -、-CH 2 CH 2 CH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 Etc. C (C) 1-10 Alkyl refers to an alkyl group having 1 to 10 carbon atoms, in particular embodiments, C 1-10 The number of carbon atoms of the alkyl group may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
"halogen" refers to elements of group VIIA of the periodic Table of elements, including elements such as chlorine (Cl), bromine (Br), iodine (I), and the like.
"hydroxy" refers to a group containing only two atoms, oxygen and hydrogen, of the formula-OH.
"amino" refers to a group containing only two atoms, nitrogen and hydrogen, of the formula-NH 2 。
"carboxyl" refers to a group containing only three atoms of carbon, oxygen, and hydrogen, and has the chemical formula-COOH.
"acyl halide" refers to a group containing three atoms of carbon, oxygen and chlorine, and has the chemical formula-COCl.
"isocyanate" refers to a group containing three atoms of carbon, nitrogen, and oxygen, and has the chemical formula-n=c=o.
In order to make the objects, technical solutions and advantages of the present application more apparent, the present application will be further described in detail with reference to examples. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the present application.
The present application provides a carrier comprising: dermatan sulfate and a thioketal compound connected with the dermatan sulfate, wherein the structure of the thioketal compound is shown as a formula (I):
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 And R is 8 Each independently selected from hydrogen, C 1-10 At least one of alkyl, hydroxy, amino, carboxyl, halogen, R 9 And R is 10 And X and Y are each independently selected from at least one of carboxyl, hydroxyl, amino, acyl halide and isocyanate groups.
Specifically, dermatan sulfate is a glycosaminoglycan composed of repeating disaccharide units, and its disaccharide units are composed of 2-ethylamino-4-sulfuric acid-D-galactose and L-iduronic acid. The dermatan sulfate has excellent bionic homing targeting on melanoma, has good specificity in targeting melanoma, is favorable for improving the concentration of the medicine at the melanoma part, enhances the induction effect of the medicine on ICD and enhances the anti-tumor immune response.
In some embodiments, dermatan sulfate has a structure according to formula (II):
wherein m and n represent the degree of polymerization, m+n=64, and m/n is not less than 1.
The dermatan sulfate used in the embodiment of the application can be obtained through market purchase, can also be obtained through synthesis by adopting a conventional technical means in the field, can be flexibly selected according to practical experiments and economic conditions, and has specific sources which do not influence the performance and effect of the carrier.
The dermatan sulfate is used as a main body material of a carrier in the embodiment of the application, and the thioketal compound is used as a functional molecule to modify the dermatan sulfate, so that the problem that the dermatan sulfate cannot load a hydrophobic drug due to strong hydrophilicity is solved, and the dermatan sulfate with homing targeting activity on melanoma is possible to be used as a carrier of the hydrophobic drug.
In the embodiment of the application, the structure of the thioketal compound is shown as a formula (I):
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 And R is 8 Each independently selected from hydrogen, C 1-10 At least one of alkyl, hydroxy, amino, carboxyl, halogen, R 9 And R is 10 And X and Y are each independently selected from at least one of carboxyl, hydroxyl, amino, acyl halide and isocyanate groups.
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 And R is 8 As the substituent groups on the fluorene ring, the types of the substituent groups, preferably R, can be flexibly adjusted according to the types of drug molecules and the synthesis difficulty of the carrier in the drug delivery system to be constructed 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 And R is 8 Each independently selected from hydrogen, C 1-5 Alkyl, thus, to ensure that the thioketal compound has good hydrophobicity.
R 9 And R is 10 For the hydrophobic alkyl chain connected to the S atom, alkyl with the number of carbon atoms being larger than 1 is selected, and the types of the hydrophobic alkyl chains can be flexibly adjusted according to the hydrophobicity of drug molecules in a drug delivery system to be constructed and the difficulty of carrier synthesis.
X and Y are active functional groups attached to the hydrophobic alkyl chain, each independently selected from at least one of carboxyl, hydroxyl, amino, acyl halide and isocyanate groups, through which physical and/or chemical attachment to dermatan sulfate is achieved.
The thioketal compound has fluorene ring, thioketal structure and active functional groups such as carboxyl, hydroxyl, amino and the like, and has excellent Reactive Oxygen Species (ROS) response activity, and can be used as ROS response units, so that the thioketal compound can be hydrolyzed at focus positions to realize drug release, and is synergistic with dermatan sulfate, so that on one hand, the concentration of the drug at the melanoma positions is favorably improved, the induction effect of the drug on ICD is enhanced, the anti-tumor immune response is enhanced, on the other hand, the side effects of other organs caused by the non-specific distribution of the drug are avoided, and meanwhile, various intermolecular interactions such as hydrophobic interaction among alkyl groups, hydrogen bond, pi-pi stacking hydrophobic interaction, pi-anion electrostatic interaction and the like can be provided, the carrier and a plurality of hydrophobic drugs provided by the application can be induced and promoted to construct nano chemical immunotherapy drugs in a self-assembly mode, the drug loading capacity is effectively improved, and a nano target therapy system responding to tumor microenvironment is constructed.
In some embodiments, the thioketal is selected from any one of the following:
the manner of attachment of the thioketal compound to dermatan sulfate can be adjusted based on the type of X, Y, either physically or chemically. When the thioketal compound is physically linked to dermatan sulfate, the physical means may be hydrogen bonding; when the thioketal compound is chemically linked to dermatan sulfate, the chemical means is a chemical bond.
In some embodiments, the thioketal is linked to dermatan sulfate with a chemical bond comprising at least one of an ester bond, an ether bond, an amide bond, and a carbonate bond. The synthesis method of the chemical bonds is simple, and can promote the firm connection of the thioketal compounds on dermatan sulfate.
The thioketal compound is grafted onto the dermatan sulfate, so that the dermatan sulfate is taken as a carrier to load the hydrophobic drug, and the carrier has ROS response performance, thereby successfully constructing a nano target therapy system responding to the tumor microenvironment.
To a certain extent, the grafting rate of the thioketal compound influences the function of the carrier. In some embodiments, 32-192 molecules of the thioketal compound are attached per molecule of the dermatan sulfate. By controlling the dosage of the thioketal compound in the above range, the carrier can be ensured to have enough hydrophobicity to be assembled with most of hydrophobic drugs to form nanoparticles, and the carrier can be ensured to have good ROS response performance. Preferably, the amount of the thioketal compound linked per molecule of dermatan sulfate is 0.5 to 3 times the sum of m and n based on the dermatan sulfate having the structure represented by the formula (II).
The method for grafting the thioketal compound onto the dermatan sulfate comprises various methods, and the method can be adjusted according to the specific structure of the thioketal compound and experimental conditions.
In some embodiments, the synthetic route for grafting thioketal compounds onto dermatan sulfate includes:
s01, dermatan sulfate, thioketal compounds and a catalyst form a mixed system;
s02, adding a condensing agent into the mixed system formed in the step S01, and then carrying out reaction.
The types of the catalyst and the condensing agent refer to the specific structures of dermatan sulfate and thioketal compounds, and in one embodiment, the dermatan sulfate has a structure as shown in formula (II) 1 ) As shown, the thioketal compound is selected as ATK, and the ATK has a structure shown as formula (I) 1 ) The catalyst is 4-dimethylaminopyridine, and the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide.
The carriers provided in the embodiments of the present application are nanospheres, and in some embodiments, have a particle size of 30-900nm. When the particle size is smaller than 30nm, the specific surface area of the carrier particles is too large, and the surface potential energy is too high, so that the particles are agglomerated; when the particle size is larger than 900nm, the transport and uptake in the living body are affected.
In summary, the carrier provided by the embodiment of the application is mainly composed of dermatan sulfate and thioketal compounds, the dermatan sulfate has excellent bionic homing targeting on melanoma, has good specificity on targeting melanoma, has excellent Reactive Oxygen Species (ROS) response activity as shown in a formula (I), can hydrolyze focus positions to realize drug release, and cooperates with dermatan sulfate, so that on one hand, the concentration of the drug at the melanoma positions is favorably improved, the induction effect of the drug on ICD is enhanced, the antitumor immune response is enhanced, on the other hand, the non-specific distribution of the drug is avoided to cause other organ side effects, in addition, the thioketal compounds are adopted to functionally modify dermatan sulfate, the problem that the dermatan sulfate cannot load hydrophobic drugs due to strong hydrophilicity is solved, and meanwhile, due to the structural characteristics of the thioketal compounds, the carrier and a plurality of hydrophobic drugs provided by the application can be induced and promoted to self-assemble the bionic nano-chemotherapy drugs to construct the drug, the drug loading capacity is effectively improved, and a nano target system responding to tumor microenvironment is constructed.
Based on the carrier provided in the foregoing embodiments, embodiments of the present application further provide a drug delivery system, including: an effective dose of the drug molecules and a carrier for loading the drug molecules, wherein the carrier is the carrier.
The drug delivery system provided by the embodiment of the application can be applied to chemotherapy of melanoma based on the carrier, has the characteristics of high immune response, low toxic and side effects, high drug loading capacity and stable system, can carry most of hydrophobic drugs, has a wide application range and has good market application prospect.
Specifically, the drug molecules are active molecules having applications such as prevention, diagnosis and treatment of diseases, and in the examples of the present application, the drug molecules mainly refer to hydrophobic drugs.
In some embodiments, the drug molecule is a hydrophobic anti-tumor drug selected from at least one of doxorubicin, epirubicin, daunorubicin, mitoxantrone, camptothecin, irinotecan.
In the drug delivery system provided in the embodiments of the present application, drug molecules are mainly connected to a carrier through a non-covalent bond, for example, through interactions of various intermolecular forces such as hydrophobic interactions between alkyl groups, hydrogen bonds, pi-pi stacking hydrophobic interactions, pi-anion electrostatic interactions, and the like. Further, the drug molecules are embedded in the carrier, the drug molecules and the thioketal compound of the carrier form a hydrophobic core, and the dermatan sulfate of the carrier forms a hydrophilic shell.
The preparation method of the above-mentioned drug delivery system may refer to a conventional procedure in the art, for example, dispersing a drug molecule and a carrier in a hydrophilic medium, so that the carrier as an amphiphilic polymer and a hydrophobic drug are self-assembled in the hydrophilic medium, specifically, hydrophobic part of the thioketal compound in the carrier structure and the hydrophobic drug undergo various intermolecular interactions, the hydrophobic drug and the thioketal compound of the carrier form a hydrophobic core, and dermatan sulfate of the carrier forms a hydrophilic shell, and then dialysis is performed.
It is understood that the hydrophilic medium is also called hydrophilic solvent, and is a solvent containing polar groups, including but not limited to water, N-dimethylformamide (abbreviated as DMF), dimethyl sulfoxide (abbreviated as DMSO), etc.
In embodiments of the present application, the particular dosage form of the drug delivery system provided is not limited and may be adapted to the particular use of the drug molecule and the needs of the condition, such as in some embodiments the drug delivery system is an injectable formulation. More specifically, the injectable formulation may be delivered locally or systemically, and may be administered to a subject in need thereof via oral administration, intravenous injection, intravenous infusion, intraperitoneal injection, intramuscular injection, and/or subcutaneous injection. The drug delivery system can be expressed as a solid preparation or a liquid preparation, and is prepared into a corresponding injection by adopting normal saline before use, and then is injected into a human body through injection equipment, so that the drug delivery system has good biocompatibility, is convenient to operate and is convenient for clinical use.
On the basis of the above embodiments, the drug delivery system provided in the embodiments of the present application may further include: pharmaceutically acceptable excipients, including but not limited to pharmaceutically acceptable carriers, solvents, excipients, buffers, stabilizers, and the like. In some embodiments, the carrier is at least one of sugar, starch, cellulose and its derivatives, tragacanth powder, maltose, gelatin and talc. In some embodiments, the excipient is at least one of cocoa butter, suppository wax, oil, glycols, esters, and agar. In some embodiments, the buffer is selected from at least one of magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, ringer's solution, ethanol, and phosphate buffered solution.
Further, the embodiment of the application also provides application of the carrier or the drug delivery system in preparation of anti-melanoma drugs.
Experiments prove that the drug delivery system constructed by the carrier provided by the embodiment of the application has good activity of inhibiting the growth of melanoma at both a cellular level and an animal level, and has application prospect of preparing anti-melanoma drugs.
In order that the details of the above-described implementations and operations of the present application may be clearly understood by those skilled in the art, and that the advanced performance of the carriers, drug delivery systems and applications provided by the examples of the present application are notably embodied, embodiments of the present application are illustrated below by way of examples.
In the following examples, dermatan sulfate is shown as DS, and has the structure shown as formula (II) 1 ) Shown, and m/n=1; the thioketal compound is ATK; 4-dimethylaminopyridine is denoted DMAP; n, N-dimethylformamide is designated DMF; 1-ethyl- (3-dimethylaminopropyl) carbodiimide is denoted EDC; doxorubicin is denoted DOX.
Example 1
This example prepares a vector formed by the attachment of ATK to DS, labeled ADS, and the following specific preparation processes:
s11, under the protection of nitrogen, 3g of DS, 108mg of DMAP and 1290mg of ATK are dissolved in anhydrous DMF to form a first mixed solution;
s12, dissolving 500mg of EDC in 5mL of DMF, slowly dripping the solution into the first mixed solution under ice bath condition, reacting for 48 hours under magnetic stirring condition, slowly dripping the obtained reaction solution into a large amount of glacial diethyl ether, and immediately generating a large amount of precipitation; then filtering to obtain a filter cake, repeatedly washing the filter cake with glacial ethyl ether, and drying to obtain a target product ADS, wherein the target product ADS has the following chemical structure:
example 2
This example prepares a drug delivery system formed from ADS and DOX, labeled DOX/ADS NP, following specific preparation procedures:
dissolving 30mg of ADS and 10mg of DOX together in DMF, loading into a dialysis bag with a cut-off molecular weight of 1000Da, dialyzing with deionized water for 48 hours, and lyophilizing the liquid in the dialysis bag to obtain DOX/ADS NP.
Comparative example 1
The difference between this comparative example and example 1 is that: replacing ATK with UTK, and marking the obtained product as UDS;
the chemical structure of UTK is as follows:
the chemical structure of UDS is as follows:
comparative example 2
The difference between this comparative example and example 2 is that: ADS was replaced with UDS prepared in comparative example 1, and the resulting product was labeled DOX/UDS NP.
Test example 1
ADS prepared in example 1 and UDS prepared in comparative example 1 were taken as test samples, and their nuclear magnetic resonance hydrogen spectra were respectively tested.
FIG. 1 shows the nuclear magnetic resonance hydrogen spectra of ADS and UDS, and ATK and UTK were successfully attached to DS, respectively, as shown.
The following are nuclear magnetic resonance hydrogen spectrum data of ADS:
1 H NMR(600MHz,DMSO-d 6 )δ7.73(d,2H,Ar-H),7.55(d,2H,Ar-H),7.37-7.33(t,4H,Ar-H),4.35-4.26(s,4H,-CH 2 -OCO-),2.27-2.25(t,4H,-S-CH 2 -CH 2 -),2.06-2.04(t,4H,CH 2 -CH 2 -COOH),1.83(s,6H,CH 3 CO-NH-),1.38-1.35(t,4H,-S-CH 2 -CH 2 -)；
the following are nuclear magnetic resonance hydrogen spectrum data of UDS:
1 H NMR(600MHz,DMSO-d 6 )δ4.36-4.26(s,4H,-CH 2 -OCO-),2.13(t,4H,-(CH 2 ) 5 -CH 2 -CH 2 -COOH),1.83(s,6H,CH 3 CO-NH-),1.40(m,4H,-(CH 2 ) 5 -CH 2 -CH 2 -COOH)),1.14(br,10H,-(CH 2 ) 5 -CH 2 -CH 2 -COOH)。
test example 2
ADS prepared in example 1 and UDS prepared in comparative example 1 were taken as test samples, the test samples were dissolved in DMF, put into dialysis bags with a molecular weight cut-off of 1000Da, dialyzed against deionized water for 48 hours, and the liquids in the dialysis bags were lyophilized to obtain nanoparticle ADS NP and UDS NP, respectively, by the above-mentioned method.
1. ADS NP was dispersed in PBS buffer and Hydrogen peroxide (1 mmol/L, H) 2 O 2 ) In the process, a Transmission Electron Microscope (TEM) is adopted to observe the microscopic morphology, and then the particle size distribution of ADS NP before and after being dispersed in hydrogen peroxide is tested.
FIG. 2 is a TEM image of ADS NP in buffer and hydrogen peroxide, as shown in the figure, ADS NP is subjected to H 2 O 2 Disintegration occurs after treatment and the morphology becomes non-uniformRules. Fig. 3 shows particle size distribution of ADS NP before and after dispersing in hydrogen peroxide, and as shown in the figure, the ADS NP changes significantly after incubating in hydrogen peroxide, and the particle size becomes smaller. The results of fig. 2 and 3 are combined to show that the carrier provided by the application has obvious active oxygen responsive hydrolysis capability.
2. Detection of ADS NP at different H 2 O 2 The hydrolysis in hydrogen peroxide solution with concentration is controlled by PBS buffer solution (pH 7.4), and FIG. 4 shows the detection result, and the hydrolysis rate of ADS NP is shown as follows H in hydrogen peroxide solution 2 O 2 The concentration increases.
3. Detection of ADS NP and UDS NP in superoxide anion (O) 2 - ) Hydroxyl radical (OH), hypochlorite (OCl) - ) Nitrite peroxide (ONOO) - ) And hydrogen peroxide (H) 2 O 2 ) The hydrolysis conditions in different ROS environments are compared with PBS buffer (pH 7.4), and the detection result is shown in FIG. 5, wherein the ADS NP is obviously hydrolyzed in different active oxygen solutions, so that the ADS NP has obvious active oxygen response hydrolysis capability.
Test example 3
The DOX/ADS NP prepared in example 2 and the DOX/UDS NP prepared in comparative example 2 were taken as test samples, and performance tests were performed, respectively.
1. The DOX/ADS NP and DOX/UDS NP were dispersed in PBS buffer solution, and the microscopic morphology was observed by Transmission Electron Microscopy (TEM), and FIG. 6 is a TEM image of the DOX/ADS NP and DOX/UDS NP in the buffer solution.
2. FIG. 7 shows the results of DOX/ADS NP and DOX/UDS NP Drug Loading (DLC) and drug Encapsulation Efficiency (EE) tests, wherein the DOX/ADS NP has higher drug loading and drug encapsulation efficiency than the DOX/UDS NP, indicating that the ATK modified DS can significantly enhance the drug loading capacity and the ADS can significantly enhance the loading to DOX. Wherein, the calculation formula of the drug load is the mass of the drug in the nano-particles divided by the mass of the nano-particles, and the calculation formula of the drug encapsulation efficiency is the mass of the drug in the nano-particles divided by the total drug feeding mass.
3. FIG. 8 is an ultraviolet scan pattern of DOX, DOX/ADS NP and DOX/UDS NP, showing a red shift in DOX/ADS NP, indicating pi-pi stacking between DOX and ATK.
4. FIG. 9 shows the relative particle size change of DOX/ADS NP in the presence of potassium chloride (KCl), urea (Urea), and Sodium Dodecyl Sulfate (SDS), the relative particle size is the ratio of the measured particle size to the particle size before testing, and as shown in the figure, the DOX/ADS NP particle size is mutated in the presence of SDS, indicating that the hydrophobic force is the main driving force in the self-assembly process of DOX and ADS.
5. Using AutoDock software, the interaction relationship between DOS and ATK was simulated, FIG. 10 is a molecular docking simulation between DOS and ATK, as shown, there are various intermolecular interactions between DOS and ATK, including hydrophobic interactions between alkyl groups, hydrogen bonds, pi-pi stacking hydrophobic interactions, pi-anionic electrostatic interactions, etc.
Test example 4
The anti-tumor activity test at the cellular level was performed using B16F10 cells as a melanoma cell model, DOX/ADS NP prepared in example 2 and DOX/UDS NP prepared in comparative example 2 as test samples, and PBS and DOX as control samples, respectively.
FIG. 11 shows the results of flow assays for apoptosis of B16F10 cells after each sample was used. As shown in the figure, DOX/ADS NP can obviously improve apoptosis of B16F10 cells by DOX.
Test example 5
A melanoma mouse model is constructed, DOX/ADS NP prepared in example 2 and DOX/UDS NP prepared in comparative example 2 are taken as test samples, PBS and DOX are taken as control samples, and anti-tumor activity tests at animal level are respectively carried out.
FIG. 12 shows that DOX/ADS NP significantly inhibited tumor growth and increased drug DOX concentration at the site of melanoma, corresponding to tumor changes in mice and weight changes in mice after application of each sample.
FIG. 13 shows mature dendritic cells (CD 80) in perineoplastic lymph node tissue of corresponding mice after application of each sample + CD86 + ) As shown in the figure, DOX/ADS NP can obviously improve the DOX induction of tumor perilymph by the medicineThe ability of dendritic cells to mature in the junction.
FIG. 14 is CD in spleen tissue of corresponding mice after application of each sample 3+ CD 4+ T cells and CD 3+ CD 8+ As shown in the results of flow analysis of T cells, DOX/ADS NP can obviously improve the capacity of the drug DOX to induce helper T cells and killer T cells in spleen.
The foregoing description of the preferred embodiments of the present application is not intended to be limiting, but is intended to cover any and all modifications, equivalents, and alternatives falling within the spirit and principles of the present application.
Claims (4)
1. A carrier, the carrier comprising: dermatan sulfate and thioketal compounds connected with the dermatan sulfate,
wherein, the thioketal compound is:
；
the dermatan sulfate has a structure shown in a formula (II):
and 32-192 molecules of the thioketal compound are connected to each molecule of the dermatan sulfate.
2. The carrier of claim 1, wherein the thioketal compound is linked to the dermatan sulfate with a chemical bond comprising an ester bond.
3. The carrier according to any one of claims 1 to 2, characterized in that the carrier is a nanosphered polymer; and/or
The particle size of the carrier is 30-900nm.
4. Use of a vector according to any one of claims 1 to 3 for the preparation of an anti-melanoma medicament.
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