CN117100876A - Nanocapsule for brain delivery system, preparation method and application thereof - Google Patents

Nanocapsule for brain delivery system, preparation method and application thereof Download PDF

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CN117100876A
CN117100876A CN202210388350.4A CN202210388350A CN117100876A CN 117100876 A CN117100876 A CN 117100876A CN 202210388350 A CN202210388350 A CN 202210388350A CN 117100876 A CN117100876 A CN 117100876A
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brain
naloxone
delivery system
nanomaterials
nanocapsule
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严然
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Shanghai Bajiuba Biotechnology Co ltd
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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
    • A61K47/58—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 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/38—Albumins
    • A61K38/385—Serum albumin
    • 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
    • A61K47/54—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 compound
    • A61K47/545—Heterocyclic compounds
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6925—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a microcapsule, nanocapsule, microbubble or nanobubble

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Abstract

The invention relates to a nanocapsule for a brain delivery system, a preparation method and application thereof, and belongs to the technical field of nano medicines. The invention takes 2-methacryloxyethyl phosphorylcholine and N- (3-aminopropyl) methacrylamide as monomers, N, N' -methylenebisacrylamide as a cross-linking agent, utilizes a nano material formed by free radical polymerization, takes bovine serum albumin as model protein to wrap the inside of the nano material to form a nano capsule, modifies naloxone molecules on the surface of the nano capsule, utilizes the nano capsule to specifically combine with brain opioid receptors, and forms a novel protein drug nano carrier which efficiently spans blood brain barriers through receptor mediation.

Description

Nanocapsule for brain delivery system, preparation method and application thereof
Technical Field
The invention relates to a nanocapsule for a brain delivery system, a preparation method and application thereof, and belongs to the technical field of nano medicines.
Background
The Blood Brain Barrier (BBB) is a physiological barrier that protects the brain from blood toxins and infectious agents. It is composed mainly of endothelial cells, pericytes and astrocytes. If not actively transported, the blood brain barrier may block 98% of the molecules from passing. The blood brain barrier is thus an obstacle to the surmounting of drug delivery to the brain.
In recent years, scientists have proposed various strategies to circumvent the blood brain barrier. For example, by adsorption mediated brain targeting, because the negatively charged BBB can interact with positively charged drug delivery systems on the basis of electrostatic effects, thereby facilitating the passage of drugs across the blood brain barrier. However, poor selectivity is an inherent disadvantage of adsorption-mediated targeting, as most biofilms are negatively charged. For this reason, adsorption-mediated targeting is rarely used for systemic administration. Furthermore, compounds or nanoparticles can be allowed to diffuse directly into the brain by temporarily opening the BBB. Although the BBB can be temporarily opened by several physical or chemical methods, these methods all create some damage to the BBB.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art, and provides a nanocapsule for a brain delivery system, a preparation method and application thereof.
The invention solves the technical problems through the following technical scheme: the invention firstly provides a nanomaterial for a brain delivery system, which consists of a nano capsule modified by a naloxone hydrochloride derivative. The naloxone hydrochloride derivative has a free carboxyl group. The nanocapsule is formed by 2-methacryloyloxyethyl phosphorylcholine, N- (3-aminopropyl) methacrylamide, N' -methylenebisacrylamide, ammonium persulfate and tetramethyl ethylenediamine and takes bovine serum albumin as model protein.
Endogenous opioid peptides are mainly beta-endorphins (beta-EP), and are distributed in the hypothalamus, pituitary, cortex, brain stem, diaphragm and cerebrospinal fluid. The β -EP in the blood is mainly released by the pituitary gland, and it plays an important regulatory role in analgesia, endocrine activity, neuropsychiatric and respiratory circulatory systems. Naloxone hydrochloride, a derivative of oxymorphone, is a pure antagonist of opioid receptors without agonistic activity, has greater affinity to opioid receptors than morphine and enkephalin, and can competitively block and replace opioid binding to the receptors. The naloxone has high fat solubility, and can be rapidly distributed throughout the body, especially in brain, heart, lung and kidney, and the distribution in brain after administration for 5 min is 4-6 times higher than that of blood plasma.
Thus, based on the property of naloxone to readily cross the BBB, combining it with nanocapsules that can improve drug stability to form novel protein drug nanocarriers that efficiently cross the BBB mediated by opioid receptors, the use of such novel nanocarriers would provide a new solution for drug delivery across the BBB brain.
The invention further provides a preparation method of the material, in particular to a preparation method of a nano material for a brain delivery system, which comprises the following steps:
firstly, modifying a free carboxyl group from a hydroxyl group on a benzene ring of a naloxone molecule;
step two, 2-methacryloyloxyethyl phosphorylcholine and N- (3-aminopropyl) methacrylamide are used as monomers, N, N' -methylenebisacrylamide is used as a cross-linking agent, ammonium persulfate and tetramethyl ethylenediamine are used as an initiator, a nano material is prepared through free radical polymerization, bovine serum albumin is used as a model protein, and a nano capsule is formed;
and thirdly, coupling the compound in the first step with the nanocapsule in the second step to obtain the nanocapsule with naloxone as the surface modification.
In the first step of the method, the modification step is that naloxone is reacted with bromoacetic acid tert-butyl ester to obtain intermediate compound naloxone-acetic acid tert-butyl ester, namely compound 1 is shown in figure 1 (B); the tert-butyl group of compound 1 was removed with trifluoroacetic acid to give the free carboxyl group, compound 2, fig. 1 (C). The reaction is as follows:
in the second step, 2-methacryloyloxyethyl phosphorylcholine, N- (3-aminopropyl) methacrylamide, N' -methylenebisacrylamide, ammonium persulfate, tetramethyl ethylenediamine, bovine serum albumin=10000: 10:5000:300:10:1, sequentially adding 2-methacryloyloxyethyl phosphorylcholine, N- (3-aminopropyl) methacrylamide, N' -methylenebisacrylamide, tetramethyl ethylenediamine, bovine serum albumin and ammonium persulfate into a centrifuge tube according to the sequence of the components, reacting on a shaking table overnight, and purifying and removing free proteins through a hydrophobic column to obtain the nanocapsule.
In the third step, naloxone modified compound 2 is first dissolved in 1 XPBS, the pH is adjusted to 5-6 by using a dilute HCL solution, 1.2 times of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is added, after about 1min, the pH is adjusted to about 8-9 by using a dilute NaOH solution, 1.2 times of N-hydroxysuccinimide is added, and 2-3min, and nanocapsules are added in a ratio of nanocapsules to compounds 2=1:100. The concentration of the nanocapsules is based on the concentration of the protein they encapsulate.
The invention still further provides for the use of nanomaterials for brain delivery systems, including the use of nanomaterials in the preparation of brain targeted drugs.
The application also comprises the application of the nano material in preparing the medicine for delivering the macromolecule therapeutic medicine to the brain disease part.
The invention takes 2-Methacryloxyethyl Phosphorylcholine (MPC) and N- (3-aminopropyl) methacrylamide (APM) as monomers N, N' -methylene Bisacrylamide (BIS) as cross-linking agents, ammonium Persulfate (APS) and tetramethyl ethylenediamine (TEMED) as initiators, utilizes a nano material formed by free radical polymerization, takes Bovine Serum Albumin (BSA) as model protein to wrap inside the nano material, forms nano capsules, and utilizes specific combination of the nano capsules and brain opioid receptors to form a novel protein drug nano carrier which is mediated by the receptors and efficiently spans the blood brain barrier.
Through research, the large molecular protein can be effectively transported to the brain. BSA was up to 8 times higher in brain aggregates after loading the modified naloxone nanocapsules compared to native BSA. Meanwhile, compared with the nBSA-PMPC nano-carrier with the brain targeting function studied before, the nBSA-PMPC-Naloxone nano-particle modified with Naloxone has better brain targeting effect no matter in tail vein, eye drop and nose drop administration.
Drawings
FIG. 1 naloxone modification procedure.
FIG. 2 is an H-NMR spectrum of Compound B.
FIG. 3 is an H-NMR spectrum of Compound C.
FIG. 4 MALDI-TOF MS spectrum of BSA.
FIG. 5 MALDI-TOF MS spectrum of BSA-Naloxone.
FIG. 6 DLS measurement of nBSA-PMPC-Naloxone and BSA.
FIG. 7 TEM of nBSA-PMPC-Naloxone.
FIG. 8 shows Zeta potential of nBSA-PMPC-Naloxone and BSA
FIG. 9 fluorescence imaging of brain tissue of mice administered nBSA-PMPC and nBSA-PMPC-Naloxone via the tail vein.
FIG. 10 fluorescent imaging ROI quantification of brain tissue of mice administered with nBSA-PMPC and nBSA-PMPC-Naloxone by tail vein.
FIG. 11 fluorescence intensity of brain tissue milling solutions of mice administered with nBSA-PMPC and nBSA-PMPC-Naloxone via tail vein.
FIG. 12 is a fluorescence imaging of brain tissue of mice administered with nBSA-PMPC and nBSA-PMPC-Naloxone by ocular administration.
FIG. 13 fluorescent imaging ROI quantification of brain tissue of mice by ocular administration of nBSA-PMPC and nBSA-PMPC-Naloxone.
FIG. 14 fluorescence intensity of brain tissue milling solutions of mice administered with nBSA-PMPC and nBSA-PMPC-Naloxone by eye.
FIG. 15 is a fluorescence imaging of brain tissue of mice given nBSA-PMPC and nBSA-PMPC-Naloxone by nasal administration.
FIG. 16 fluorescent imaging ROI quantification of brain tissue of mice given nBSA-PMPC and nBSA-PMPC-Naloxone by nasal administration.
FIG. 17 fluorescence intensity of brain tissue milling solutions of mice administered with nBSA-PMPC and nBSA-PMPC-Naloxone via nasal cavity.
Detailed Description
The following will describe the technical scheme of the embodiment of the present invention clearly and completely.
Examples
1. Modification of naloxone
The experimental steps are as follows:
(1) The reaction time was about 2h as monitored by TLC by adding potassium carbonate (1518.8 mg) of fig. 1A (800 mg,2.198 nmol) and 5 eq to 10 ml acetonitrile and stirring at 50 degrees for 30 min, followed by the addition of 2 eq t-butyl bromoacetate to raise the temperature to 90 degrees. The reaction solution was filtered and the resulting liquid phase was subjected to rotary evaporation to give a yellow oily liquid which was purified by column chromatography on silica gel (mobile phase dichloromethane: methanol=20:1). The H-NMR of compound B is shown in FIG. 2.
(2) 2 ml trifluoroacetic acid was added to FIG. 1B (100 mg\0.226 nmol) and stirred at room temperature for 1 h, and after completion of the TLC detection reaction, 5 ml chloroform was added three times each time and rotary evaporation was performed. The obtained compound was then added with about 1. 1ml ethanol by rotary evaporation with 5.5 ml diethyl ether added twice each time, and then diethyl ether was added in an amount of about 50 times the volume of ethanol to precipitate a white solid. The white solid obtained by suction filtration is the compound C in figure 1. The H-NMR of compound C is shown in FIG. 3.
2. Synthesis of nanocapsules
BSA was dissolved in 1 XPBS, then MPC, APM, BIS (10000:10:5000:300:10:1, n/n, MPC: APM: BIS: BSA) was added to the solution, then APS (500:1, n/n, APS: BSA) and TEMED (1000:1, n/n, TEMED: BSA, pH=7.0) were added to initiate free radical polymerization, and reaction was carried out at room temperature for 2h. To obtain nBSA-PMPC. Purification and separation by hydrophobic column
3. Coupling of naloxone with nanocapsules
After dissolving compound C in 1 XPBS, the pH was adjusted to about 5-6 with dilute HCl solution. And after adding the corresponding amount of EDC, the pH is adjusted to about 8-9 by dilute NaOH, and then NHS is added. Finally adding nBSA-PMPC (100:1.2:1.2:1, n/n, compound C: EDC: NHS: nBSA-PMPC), carrying out shaking reaction 12h, and dialyzing to obtain the nBSA-PMPC-Naloxone.
4. Characterization of nanocapsules
And taking nano-capsules 1mL dialyzed in PB solution, and carrying out dynamic light scattering test by using a Malvern Zetasizer Nano ZSE instrument to obtain zeta potential of the nano-capsules.
Cy7 fluorescent markers
(1) Under the dark condition, 1 mg of sulfo-Cy7-NHS is dissolved in 200 mu l of DMSO with the final concentration of 5 mg/ml, wrapped by aluminum foil paper and placed in a refrigerator at the temperature of minus 20 ℃ to be frozen in dark for later use.
(2) After adding ulfo-Cy7-NHS to the system in a molar ratio of 1:3, nBSA-PMPC and NaOH solution were adjusted to pH=8, and the reaction was carried out by shaking at room temperature under dark conditions for 4 h.
(3) Dialyzing at room temperature in dark place, changing dialysate every 4h, and dialyzing for 12h.
1. Detailed description of the preferred embodiments
6. Tissue imaging
(1) Tail vein injection administration: 8 mice were taken and divided into two groups of 4 mice each, an experimental group (nBSA-PMPC-Naloxone) and a control group (nBSA-PMPC), and after each administration of 25.5. 25.5 mg/kg and 10 h, the mice were heart perfused, and brain tissues were taken for fluorescence imaging.
(2) Nasal administration: 8 mice were taken, and each group was divided into two groups of 4 groups of experimental group (nBSA-PMPC-Naloxone) and control group (nBSA-PMPC), 50. Mu.l of sample was added dropwise to the nasal cavity of the mice by a pipette, and after each administration of 6.4 mg/kg and 10 h, the mice were subjected to cardiac perfusion, and brain tissues were taken for fluorescence imaging.
(3) Ocular drug administration: 8 mice were taken, and each group was divided into two groups of 4 groups of experimental group (nBSA-PMPC-Naloxone) and control group (nBSA-PMPC), 50 μl of sample was added dropwise to both eyes of the mice by a pipette, 1.28mg/kg of each was administered, and after heart perfusion was performed on the mice after 10 h administration, brain tissues were taken for fluorescence imaging.
7. Fluorescence content determination
The fluorescence intensity of brain tissues is further quantitatively studied by a fluorescence enzyme-labeled instrument, and the aggregation degree of nBSA-PMPC-Naloxone-Cy7 in the brain is ascertained.
(1) The removed brain tissue was placed into 4 ml centrifuge tubes per 100 g/1ml of 1 XPBS.
(2) High throughput tissue grinder, 50 Hz,10 s, after three grinding, high speed centrifuge, get its supernatant solution.
(3) Add to a black 96-well plate, 100 μl per well.
(4) And (5) measuring by a fluorescence enzyme-labeled instrument.
8. Experimental results
The successful modification of Naloxone was demonstrated by the nuclear magnetic resonance results (fig. 2-3) through the reaction of the step of fig. 1. Successful coupling of Naloxone with BSA via a condensation reaction of carboxyl groups with amino groups was demonstrated by TOF (fig. 4-5). Particle size results for DLS (FIG. 6) found that nBSA-PMPC had a particle size of about 30 nm, which was also confirmed by TEM (FIG. 7) imaging, which was significantly larger than that of natural BSA (< 10 nm), and that the change in zeta potential of the binding protein surface (FIG. 8) all demonstrated successful synthesis of nBSA-PMPC.
To verify the targeted delivery capacity of nBSA-PMPC-Naloxone across the BBB to the brain, we first observed delivery of nBSA-PMPC-Naloxone to the rat brain by rat tail vein administration. This conclusion is further demonstrated by observation of the distribution of the fluorescently labeled samples (FIGS. 9-10) and by finding that nBSA-PMPC-dosed mouse proteins aggregate significantly less in the brain than nBSA-PMPC-Naloxone-dosed mice, the fluorescence intensity of brain tissue homogenates (FIG. 11). Further, similar results were also observed after eye drop administration (FIGS. 12-14) and nasal administration (FIGS. 15-17) in mice, with nBSA-PMPC administered mice having significantly lower protein aggregation in the brain than mice with nBSA-PMPC-Naloxone. These results demonstrate that Naloxone modified nanocapsules nBSA-PMPC-Naloxone can significantly enhance the ability of the protein cross-domain BBB to accumulate in the brain in a variety of dosing routes, which combine with nanocapsules that can enhance drug stability to form novel protein drug nanocarriers that efficiently cross the BBB mediated by opioid receptors. Its application will provide a new solution for drug delivery across the BBB brain.
In addition to the implementations described above, other implementations of the invention are possible. All technical schemes formed by equivalent substitution or equivalent transformation fall within the protection scope of the invention.

Claims (10)

1. A nanomaterial for brain delivery system, consisting of a naloxone hydrochloride derivative modified nanocapsule.
2. The nanomaterial for brain delivery system according to claim 1, characterized in that: the naloxone hydrochloride derivative has a free carboxyl group.
3. The nanomaterial for brain delivery system according to claim 1, characterized in that: the nanocapsule is formed by taking bovine serum albumin as a model protein, wherein the model protein is 2-methacryloyloxyethyl phosphorylcholine, N- (3-aminopropyl) methacrylamide, N' -methylenebisacrylamide, ammonium persulfate and tetramethyl ethylenediamine.
4. A method of preparing nanomaterials for use in a brain delivery system according to claim 1 comprising the steps of:
firstly, modifying a free carboxyl group from a hydroxyl group on a benzene ring of a naloxone molecule;
step two, 2-methacryloyloxyethyl phosphorylcholine and N- (3-aminopropyl) methacrylamide are used as monomers, N, N' -methylenebisacrylamide is used as a cross-linking agent, ammonium persulfate and tetramethyl ethylenediamine are used as an initiator, a nano material is prepared through free radical polymerization, bovine serum albumin is used as a model protein, and a nano capsule is formed;
and thirdly, coupling the compound in the first step with the nanocapsule in the second step to obtain the nanocapsule with naloxone as the surface modification.
5. The method of preparing nanomaterials for use in a brain delivery system of claim 4, wherein: in the first step, the modification step is that naloxone reacts with tert-butyl bromoacetate to obtain an intermediate compound naloxone-tert-butyl acetate, namely a compound 1; the tert-butyl group of compound 1 was removed with trifluoroacetic acid to give the free carboxyl group, compound 2.
6. The method of preparing nanomaterials for use in a brain delivery system of claim 4, wherein: in the second step, 2-methacryloyloxyethyl phosphorylcholine, N- (3-aminopropyl) methacrylamide, N' -methylenebisacrylamide, ammonium persulfate, tetramethyl ethylenediamine, bovine serum albumin=10000: 10:5000:300:10:1, sequentially adding 2-methacryloyloxyethyl phosphorylcholine, N- (3-aminopropyl) methacrylamide, N' -methylenebisacrylamide, tetramethyl ethylenediamine, bovine serum albumin and ammonium persulfate into a centrifuge tube according to the sequence of the components, reacting on a shaking table overnight, and purifying and removing free proteins through a hydrophobic column to obtain the nanocapsule.
7. The method of preparing nanomaterials for use in a brain delivery system of claim 4, wherein: in the third step, naloxone modified compound 2 is first dissolved in 1 XPBS, the pH is adjusted to 5-6 by using a dilute HCL solution, 1.2 times of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is added, after about 1min, the pH is adjusted to about 8-9 by using a dilute NaOH solution, 1.2 times of N-hydroxysuccinimide is added, and 2-3min, and nanocapsules are added in a ratio of nanocapsules to compounds 2=1:100.
8. The method of preparing nanomaterials for use in a brain delivery system of claim 7, wherein: the concentration of the nanocapsules is based on the concentration of the protein they encapsulate.
9. Use of nanomaterials for brain delivery systems, including use of nanomaterials in the preparation of brain-targeted drugs.
10. The use of nanomaterials for brain delivery systems according to claim 9, wherein: including the use of nanomaterials in the manufacture of a medicament for the delivery of macromolecular therapeutic agents to a brain disease site.
CN202210388350.4A 2022-04-14 2022-04-14 Nanocapsule for brain delivery system, preparation method and application thereof Pending CN117100876A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2363468C1 (en) * 2008-04-03 2009-08-10 Сергей Константинович Судаков Use of naloxone and naltrexone derivatives in making pain-killing drugs
CN103463617A (en) * 2013-08-27 2013-12-25 王辉 Method for synthesizing targeting radioiodine labeled thyroglotulin nano capsule
US20150045555A1 (en) * 2012-02-22 2015-02-12 Jenkem Technology Co., Ltd. (Tianjin) Conjugate of Polyethylene Gylcol and Naloxone and Pharmaceutical Composition and Use Thereof
CN113244377A (en) * 2021-04-19 2021-08-13 北京化工大学 Preparation of platelet-derived growth factor nanocapsule capable of controlled release

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2363468C1 (en) * 2008-04-03 2009-08-10 Сергей Константинович Судаков Use of naloxone and naltrexone derivatives in making pain-killing drugs
US20150045555A1 (en) * 2012-02-22 2015-02-12 Jenkem Technology Co., Ltd. (Tianjin) Conjugate of Polyethylene Gylcol and Naloxone and Pharmaceutical Composition and Use Thereof
CN103463617A (en) * 2013-08-27 2013-12-25 王辉 Method for synthesizing targeting radioiodine labeled thyroglotulin nano capsule
CN113244377A (en) * 2021-04-19 2021-08-13 北京化工大学 Preparation of platelet-derived growth factor nanocapsule capable of controlled release

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