CN116270974A - Composition, abelmoschus delivery system and preparation method - Google Patents
Composition, abelmoschus delivery system and preparation method Download PDFInfo
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- CN116270974A CN116270974A CN202310223877.6A CN202310223877A CN116270974A CN 116270974 A CN116270974 A CN 116270974A CN 202310223877 A CN202310223877 A CN 202310223877A CN 116270974 A CN116270974 A CN 116270974A
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- aflibercept
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Classifications
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- 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
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
- A61K38/179—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
- A61K47/62—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 a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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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 invention belongs to the technical field of biology, and discloses a composition for improving the capability of Abelmoschus to penetrate cornea matrix, which comprises a membrane penetrating peptide and Abelmoschus; the penetrating peptide is positively charged penetrating peptide. The composition adopts the film penetrating peptide with positive charges and the aflibercept, and the preferred film penetrating peptide can neutralize the aflibercept with negative charges, and can penetrate through cornea stroma when combined with the film penetrating peptide and the aflibercept, so that compared with the single use of the aflibercept, the capacity of penetrating through the cornea stroma is improved. Meanwhile, the invention also provides an Abelmosil delivery system which combines the advantages of the composition, and meanwhile, the composition is coated by hydrogel by adopting hydrogel formed by preferred self-assembled polypeptides, so that the retention time and the absorption rate of the composition are improved. Finally, the invention also provides a preparation method of the delivery system.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to a composition, an Abelmoschus delivery system and a preparation method.
Background
Corneal neovascularization (covv) refers to abnormal angiogenesis in clear corneal tissue. As a significant cause of vision impairment worldwide, about 4.1% -10.4% of individuals worldwide are given covv each year, with 12% -57.4% subsequently blinding. Covv arises from a variety of causes, such as hypoxia, infection, persistent inflammation, chemical or physical damage, and corneal transplants caused by contact lens wear. They share a common process of pro-angiogenic-anti-angiogenic network imbalance. Vascular Endothelial Growth Factor (VEGF) is one of the most important mediators of angiogenesis, and is upregulated in CoNV, which induces immature neovascular growth, resulting in impaired corneal transparency and visual function.
anti-VEGF treatment has been successful in treating ocular neovascular diseases. Abelmoschus (Eylea) is the most popular anti-VEGF drug, aimed at sequestering VEGF. It has been shown to be effective in preventing neo-vascularization of covv. However, conventional topical eye drops or subconjunctival injections have limited therapeutic efficacy and the bioavailability of macromolecules such as aflibercept is very low due to the variety of barrier and clearance mechanisms present on the ocular surface. High frequency administration can lead to increased systemic adverse effects, affordable costs and poor patient compliance.
To solve this problem, a method for delivering a drug to the posterior segment of the eye based on the form of eye drops is proposed by those skilled in the art, specifically:
CN114948864a discloses a method for delivering an agent to the posterior segment of an eye comprising administering to the eye a pharmaceutical composition comprising an agent and mesoporous silica nanoparticles. Also provided are an ophthalmic solution and a method for treating an ocular disease in an individual in need of such treatment.
The description is as follows: wherein the agent is a small molecule drug or a biomolecule selected from the group consisting of: polypeptides, antibodies, antibody fragments, fusion proteins, ligands, biomolecule-binding proteins, functional fragments of proteins, enzymes or nucleotides;
wherein the medicament is difluprednate (difluprednate), loteprednol (loteprednol), dexamethasone (dexamethophone), dexamethasone sodium phosphate, fluocinolone acetonide (fluocinolone), triamcinolone (triamcinolone), triamcinolone acetonide (triamcinolone acetonide), rimexolone (rimexolone), prednisolone (prednisolone), meflozone (mecrone), vitamin nipagin (vertebroxin), bevacizumab (bevacizumab), ranibizumab (ranibizumab), pipamate (pegaptanib), aflibercept (bromoxynil), bromoxynil (bromoxynil), fastfirox (fasciclesonide), acil (idebenone), idebenone (thiazocine), methimazone (trimethoprim), trimethoprim (trimethoprim), and other than the drugs.
The technical problem that the present case solves is: attempts have been made to develop a method and formulation for delivering aflibercept with a novel strategy to increase delivery efficiency and reduce delivery difficulty.
Disclosure of Invention
In view of the shortcomings of the prior art, the invention aims to provide a composition for improving the penetration of aflibercept through a cornea matrix, wherein the composition adopts a positively charged transmembrane peptide and aflibercept, and the preferred transmembrane peptide can neutralize the negatively charged aflibercept, and can penetrate through the cornea matrix in combination with the composition, so that the penetration of the aflibercept through the cornea matrix is improved compared with the single use of the aflibercept.
Meanwhile, the invention also provides an Abelmosil delivery system which combines the advantages of the composition, and meanwhile, the composition is coated by hydrogel by adopting hydrogel formed by preferred self-assembled polypeptides, so that the retention time and the absorption rate of the composition are improved.
Finally, the invention also provides a preparation method of the delivery system.
In order to achieve the aim of the invention, the invention adopts the following technical scheme: a composition for improving the ability of aflibercept to penetrate the corneal stroma comprising a transmembrane peptide and aflibercept; the penetrating peptide is positively charged penetrating peptide.
The invention adopts the membrane penetrating peptide with positive charges and the Abelmoschus, which can neutralize charges to form a closely related object, and the membrane penetrating peptide can guide the Abelmoschus to pass through the cornea stroma.
In the composition, the molar ratio of the penetrating peptide to the aflibercept is 1-10: 1.
in some embodiments, the molar ratio of the transmembrane peptide to aflibercept may be selected to be 1: 1. 2: 1. 3: 1. 4: 1. 5: 1. 6: 1. 7: 1. 8: 1. 9:1 or 10:1.
in the above composition, the membrane-penetrating peptide contains D-type amino acid.
The D-type amino acid has a larger structural corner compared with natural amino acid, so that the binding space of the D-type amino acid with the A Bai Xi general can be improved, on the premise that positive and negative charges are neutralized and substances are combined based on charge force, the larger space means that the transmembrane peptide and the A/B general can exist in a larger contact space, the binding stability is higher, and the transmembrane stability is better.
As some specific embodiments, the amino acid sequence of the membrane penetrating peptide is shown as SEQ ID No. 1; proline in the ninth position in the membrane penetrating peptide is D-type amino acid.
Meanwhile, the invention also discloses an Abelmoschus delivery system, which comprises the composition as described in any one of the above dispersed in a gel system; the gel system is formed from self-assembled polypeptides and water; the composition and gel system are compatible; by compatibility is meant that the gel system remains in a gel state after the composition is added to the gel system.
In some studies of the present invention, it was found that not all gel systems are well compatible with the composition; the delivery system of the present invention therefore only protects the combination of substances that are capable of maintaining a gel state when the composition and gel system are mixed.
Preferably, the self-assembled polypeptide has D-amino acids therein, and the self-assembled polypeptide is a positively charged self-assembled polypeptide.
The self-assembled polypeptides of the invention are positively charged, repulsive charges exist between the self-assembled polypeptides in the gel system, and can create cavities which can contain the composition, so that good compatibility between the composition and the gel is realized.
Meanwhile, the D-type amino acid has a structural corner larger than that of natural amino acid, and the hollows can be further enlarged.
By such optimization, the compatibility of the composition and the gel system and the stability of the composition released to the eyeball can be improved, and the retention time and the absorption rate of the composition can be improved.
In the Abelmosil delivery system, the concentration of the membrane penetrating peptide in the gel system is 20-200 mu M; the concentration of the self-assembled polypeptide in the gel system is 250-550 mM; the concentration of the Abelmoschus in the gel system is 10-30 mu M;
preferably, the concentration of the membrane penetrating peptide in the gel system is 30-180 mu M; the concentration of the self-assembled polypeptide in the gel system is 350-550 mM; the concentration of the Abelmoschus in the gel system is 15-25 mu M.
In some embodiments, the concentration of the transmembrane peptide in the gel system is 20 μΜ, 30 μΜ, 40 μΜ, 50 μΜ, 60 μΜ, 70 μΜ, 80 μΜ, 90 μΜ, 100 μΜ, 110 μΜ, 120 μΜ, 130 μΜ, 140 μΜ, 150 μΜ, 160 μΜ, 170 μΜ, 180 μΜ, 190 μΜ or 200 μΜ;
in some embodiments, the concentration of the self-assembling polypeptide in the gel system is 250mM, 280mM, 300mM, 350mM, 400mM, 450mM, 500mM, or 550mM;
in some embodiments, the concentration of the aflibercept in the gel system is 10 μΜ, 12 μΜ, 14 μΜ, 16 μΜ, 18 μΜ, 20 μΜ, 22 μΜ, 24 μΜ, 26 μΜ, 28 μΜ or 30 μΜ.
In some embodiments, the amino acid sequence of the transmembrane peptide is shown in SEQ ID No. 1; the amino acid sequence of the self-assembled polypeptide is shown as SEQ ID No. 2; proline arranged at the ninth position in the membrane penetrating peptide is D-type amino acid; proline in the eighth position in the self-assembled polypeptide is D-type amino acid.
In some embodiments, a buffer solution is also included;
the buffer solution is one of BTP buffer solution and PBS buffer solution.
Meanwhile, the invention also discloses a preparation method of the Abelmoschus delivery system, which comprises the following steps:
step 1: blending the membrane penetrating peptide and the Abelmosil to form a complex;
step 2: weighing self-assembled polypeptide in a centrifuge tube, adding water, and dissolving the peptide by ultrasonic;
step 3: and (3) adding the complex formed in the step (1) into the liquid in the step (2) for blending, and adding a buffer solution to form the Abelmosipu delivery system.
More specifically, the method comprises the following steps:
step 1: 1. Mu.L of the membrane-penetrating peptide and 5. Mu.L of Abelmoschus are blended to form a complex;
step 2: weighing 1mg of self-assembled polypeptide in a centrifuge tube, adding water, and dissolving the peptide by ultrasonic;
step 3: adding the complex formed in the step 1 into the liquid in the step 2 for blending, and then adding a buffer solution to form an Abelmosipu delivery system;
more specifically, the method comprises the following steps:
step 1: 1. Mu.L of the membrane-penetrating peptide and 5. Mu.L of Abelmoschus are blended for 30min at 4 ℃ to form a complex;
step 2: weighing 1mg of self-assembled polypeptide in a centrifuge tube, adding 50 mu L of water, and placing the peptide on ice by ultrasonic dissolution;
step 3: adding the complex formed in the step 1 into the liquid in the step 2 for blending, and adding 50 mu L of 2 XBTP for blending to form the Abelmosil delivery system.
Compared with the prior art, the invention has the following beneficial effects:
the composition adopts the specific penetrating peptide to match with the Abelmosil, the preferred penetrating peptide can neutralize the Abelmosil with negative charges, and the combination of the specific penetrating peptide and the Abelmosil can penetrate through cornea stroma, so that compared with the independent use of the Abelmosil, the capability of penetrating through the cornea stroma is improved.
The Abelmosil delivery system combines the advantages of the composition, and adopts the hydrogel formed by the preferred self-assembled polypeptide, and the retention time and the absorption rate of the composition are improved by wrapping the composition through the hydrogel.
The delivery system of the invention has better curative effect on cornea neovascularization and eye diseases related to neoyellow spots.
The delivery system of the present invention is most often in the form of eye drops.
Drawings
FIG. 1 is a schematic diagram of the synthesis and operation of a delivery system of the present invention;
FIG. 2 is a graph showing the effect of the inventive peptide on cell penetration;
FIG. 3 is a graph showing cytotoxicity test of the transmembrane peptide of the present invention;
FIG. 4 is a graph showing time-dependent drug release behavior of hydrogels of the present invention;
FIGS. 5A and 5B are graphs of the biocompatibility results of the delivery system of the present invention;
fig. 6 is a graph of the animal experimental effect of the delivery system of the present invention.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
The specific experimental procedures or conditions are not noted in the examples and may be followed by the operations or conditions of conventional experimental procedures described in the literature in this field. The reagents or apparatus used were conventional reagent products commercially available without the manufacturer's knowledge.
Hoechst 33343: thermo.
Example 1
Polypeptide molecules of the transmembrane peptide and the self-assembled polypeptide are synthesized by a solid-phase polypeptide synthesis method.
The sequence of the transmembrane peptide is as follows: KRVRVRVRV D PPTRVRYRVK(SEQ ID No.1)；
The sequence of the self-assembled polypeptide is as follows: vKWVKV D PPTKVKVKV-NH 2 (SEQ ID No.2)；
The method is carried out by utilizing AM resin, the needed amino acid is calculated and weighed, then the amino acid is put into a polypeptide synthesizer, and the needed molecule can be obtained by synthesizing according to related operation. Purifying by high performance liquid chromatograph, and lyophilizing to obtain corresponding dry powder target polypeptide product.
Example 2
Effect and toxicity of the transmembrane peptide
HCE-7 cells were grown at 1X 10 5 Inoculating individual cells/wells into a confocal dish; cells were allowed to attach overnight at 37 ℃,5% carbon dioxide. 10. Mu.M FITC (fluorescein isothiocyanate) labeled transmembrane peptide of example 1 (first panel of FIG. 2) and Eylea (second panel of FIG. 2) were incubated for 1 hour, and cells were stained with Hoechst for 10 minutes. Cells were washed 3 times with PBS buffer and then imaged with PBS buffer.
Referring to fig. 2, in fig. 2, merge represents the overlapping of two images represented by FITC and Hoechst, blue is a nucleus, green is a cell membrane, and the appearance of green is good in membrane penetration effect;
as can be seen from fig. 2: the penetrating peptide 1 has good penetrating property and still has good penetrating property after being mixed with Abelmoschus to form a complex
The first line of FIG. 2 shows imaging using only a 10. Mu.M concentration of transmembrane peptide after FITC labelling, after staining with Hoechst and after treatment with Merge, respectively;
the second row of FIG. 2 shows imaging after mixing with a concentration of 10. Mu.M of the transmembrane peptide and 1. Mu.M of Eylea, wherein the transmembrane peptide is labeled with FITC, after labeling with FITC, after staining with Hoechst and after treatment with Merge;
the following can be concluded from the first and second rows of fig. 2:
1. the penetrating peptide has good membrane penetration effect;
2. the addition of eyleas does not affect the membrane penetration effect of the transmembrane peptide.
HCE-7 and ARPE19 cells were plated at 5X 10 per well 3 Is inoculated into 96-well plates and adhered overnight at 37℃under 5% carbon dioxide. Fresh medium containing 0.1-500. Mu.M of penetrating peptide was used as positive control or negative control with blank medium or medium containing 0.5% DMSO, respectively.
After 24h incubation, the cells were washed and 100. Mu.L of fresh medium containing serum was added to each well. 10 μLMTT (3- (4, 5) -dimethylthiazo (-z-y 1) -3, 5-di-phenyletraculomide) was added to each well, incubated for 4h, then 150 μL DMSO was replaced with medium, and incubated with shaking at 37℃for 0.5h to promote formazan crystal dissolution. Absorbance was detected at 570nm wavelength using an ultraviolet plate reader (spectrum Max M2).
Referring to fig. 3, the transmembrane peptide was slightly toxic to cells at a concentration of 500 μm.
In conclusion, the membrane penetrating peptide has good membrane penetrability and low cytotoxicity, so that the membrane penetrating peptide has a fine function as a drug carrier.
Example 3
Drug release effect:
200. Mu.L of hydrogel was prepared after addition of varying concentration ratios of the transmembrane peptide and Elyea, and allowed to gel overnight. Then 1mL of BTP buffer (BTP 50mM, sodium chloride 150mM, pH 7.4) was added to the gel, and the mixture was placed on an incubator at 37℃and 50 rpm. At various time points, the entire buffer (1 mL) above the gel was removed and replaced with 1mL of fresh BTP buffer. Drug release was determined by coomassie brilliant blue method.
Referring to fig. 4, fig. 4 shows: hydrogels exhibited time-dependent drug release behavior, with Gel 2_1& Eylea ([ Eylea ]: 1] = 1:10) groups released about 38% at 4 hours; gel 2_1& eyread ([ eyread ]: 1] =1:1) groups released about 31% for 4 hours, both groups exhibited rapid release.
It should be noted that: the group Gel 2_1& eyleam ([ eyleam ]: 1] =1:10) refers to: the concentration of self-assembled polypeptide is 540 mu m, the concentration of penetrating peptide is 200 mu m, and the concentration of Eylea is 20 mu m;
the group Gel 2_1& eyleam ([ eyleam ]: 1] =1:1) refers to: the concentration of self-assembled polypeptide was 540 μΜ, that of transmembrane peptide was 20 μΜ, and that of eyea was 20 μΜ.
To verify the importance of the self-assembling polypeptides of the present invention, the above experiments were performed using the following commonly used self-assembling polypeptides in the art (SEQ ID Nos. 3-6), which were all able to gel alone, but gel system crashed and were unable to gel after the addition of the transmembrane peptide and Elyea.
NapFFYEE(SEQ ID No.3)、NapFFYKK(SEQ ID No.4)、NapFFYEKK(SEQ ID No.5)、NapFFYK(SEQ ID No.6)；
Wherein: the self-assembled polypeptide concentration was 540. Mu.m, the transmembrane peptide concentration was 200. Mu.m, and the Eylea concentration was 20. Mu.m.
Example 4
Biocompatibility of Gel 2_1& eyleaaggregate: live/dead staining tests were performed on hydrogels.
Specifically, 30 μl Gel 2_1& eyea Gel was dispersed into a confocal dish, which was then placed in an incubator at 37 ℃ overnight. 100. Mu.L of DMEM was added for 1 day and then incubated with HCE-7 cells for 24h. Then stained with Calcein-AM/PI and observed with confocal microscopy.
Referring to FIGS. 5A and 5B, most HCE-7 cells were positive for Calcein-AM/PI staining, indicating that: gel 2_1& Eylea Gel has good biocompatibility;
fig. 5A is a Gel 2_1& eyleaj ([ eyleaj 1] =1:10) group;
fig. 5B is a Gel 2_1& eyleaj ([ eyleaj 1] =1:1) group.
Example 5
Gel 2_1& eyleas curative effects on corneal neovascularization:
the rabbits were anesthetized. After washing the conjunctival sac with povidone-iodine solution and Balanced Salt Solution (BSS), two 7-0 nylon sutures were surgically placed in the upper quadrant of the cornea, approximately 1.0mm behind the limbus, 3.0mm across, and approximately 1/2 of the corneal depth, in the shape of "8". Gatifloxacin eye ointment is antibacterial 1 time a day for 3 consecutive days. After 5 days, the rabbit had enough corneal neovascularization in both eyes, and the establishment of the CNV animal model was considered successful. To avoid individual variability, surgical rabbit eyes were randomized into 3 groups, treated 4 times daily for 14 consecutive days according to the following formulation:
group 1: saline (NS group);
group 2: afliibept group (2 mg/mL);
group 3: gel 2_1& Eylea group.
The components of Gel 2_1& Eylea group are: the concentration of self-assembled polypeptide was 270. Mu.M, the concentration of transmembrane peptide was 200. Mu. M, eylea, and the concentration was 20. Mu.M.
Suture-induced rabbit eyeballs were treated with Gel 2_1& eyread, or Normal Saline (NS) for 14 days. After 14 days of dosing, slit lamp photographs showed that the CoNV area of the Gel 2_1& Eylea group was smaller than the other two groups.
In addition, it was found in experiments that if a transmembrane peptide of the following sequence (KVRVRVRVPPTRVRYRVK, i.e., proline at position 9 is an L-type amino acid) is used as a transmembrane peptide in a delivery system, the transmembrane efficiency is significantly reduced. This also illustrates that D-proline is very critical for maintaining delivery of eyea.
It should be noted that: although the invention does not provide other cases of Eylea concentration, the gel performance and cornea stroma have better effects in the concentration range of 10-30mM through laboratory verification.
Without being particularly bound by the present invention, the following principles are followed:
1. the amino acids are all L-type amino acids without special labeling;
2. m represents moles/liter, unless otherwise noted; mM represents millimoles per liter; mu M represents micromoles per liter.
Claims (10)
1. A composition for improving the ability of aflibercept to penetrate the corneal stroma, comprising a transmembrane peptide and aflibercept; the penetrating peptide is positively charged penetrating peptide.
2. The composition according to claim 1, wherein the molar ratio of the transmembrane peptide to the aflibercept is from 1 to 10:1.
3. the composition of claim 1, wherein the transmembrane peptide comprises a D-amino acid.
4. The composition of claim 1, wherein the amino acid sequence of the transmembrane peptide is shown in SEQ id No. 1; proline in the ninth position in the membrane penetrating peptide is D-type amino acid.
5. An aflibercept delivery system comprising the composition of any one of claims 1 to 4 dispersed in a gel system; the gel system is formed from self-assembled polypeptides and water; the composition and gel system are compatible; by compatibility is meant that the gel system remains in a gel state after the composition is added to the gel system.
6. The aflibercept delivery system of claim 5 wherein the self-assembling polypeptide has amino acid D therein and wherein the self-assembling polypeptide is a positively charged self-assembling polypeptide.
7. The aflibercept delivery system of claim 5 wherein the concentration of the transmembrane peptide in the gel system is 20 to 200 μm; the concentration of the self-assembled polypeptide in the gel system is 250-550 mM; the concentration of the Abelmoschus in the gel system is 10-30 mu M;
preferably, the concentration of the membrane penetrating peptide in the gel system is 30-180 mu M; the concentration of the self-assembled polypeptide in the gel system is 350-550 mM; the concentration of the Abelmoschus in the gel system is 15-25 mu M.
8. The aflibercept delivery system according to claim 5 wherein the amino acid sequence of the transmembrane peptide is shown in SEQ ID No. 1; the amino acid sequence of the self-assembled polypeptide is shown as SEQ ID No. 2; proline arranged at the ninth position in the membrane penetrating peptide is D-type amino acid; proline in the eighth position in the self-assembled polypeptide is D-type amino acid.
9. The aflibercept delivery system of claim 5 further comprising a buffer solution;
the buffer solution is one of BTP buffer solution and PBS buffer solution.
10. A method of preparing an aflibercept delivery system according to any one of claims 5 to 9 comprising the steps of:
step 1: blending the membrane penetrating peptide and the Abelmosil to form a complex;
step 2: weighing self-assembled polypeptide in a centrifuge tube, adding water, and dissolving the peptide by ultrasonic;
step 3: and (3) adding the complex formed in the step (1) into the liquid in the step (2) for blending, and adding a buffer solution to form the Abelmosipu delivery system.
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