CN112263684B - Anticancer prodrug, preparation method thereof and anticancer drug - Google Patents

Anticancer prodrug, preparation method thereof and anticancer drug Download PDF

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CN112263684B
CN112263684B CN202011354273.8A CN202011354273A CN112263684B CN 112263684 B CN112263684 B CN 112263684B CN 202011354273 A CN202011354273 A CN 202011354273A CN 112263684 B CN112263684 B CN 112263684B
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peg
modified gold
gold nanoclusters
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platelet membrane
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CN112263684A (en
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张晗
朵燕红
张家宜
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Shenzhen University
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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
    • A61K47/69—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
    • A61K47/6901—Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • 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
    • A61K47/59—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 otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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 provides an anticancer prodrug, which comprises platelet membrane derived vesicles (PM), PEG modified gold nanoclusters (AuNCs-PEG) and Sodium Nitroferricyanide (SNP), wherein the PEG modified gold nanoclusters and the sodium nitroferricyanide are coated in the platelet membrane derived vesicles. The invention also provides a preparation method of the anticancer prodrug and an anticancer drug. The anticancer prodrug of the invention has strong capability of being taken up by tumor cells, can also evade the immune system of organisms to smoothly enter the cancer cells, and plays the role of resisting tumors and the like.

Description

Anticancer prodrug, preparation method thereof and anticancer drug
Technical Field
The invention relates to the technical field of biological medicines, in particular to an anticancer prodrug, and also relates to a preparation method of the anticancer prodrug.
Background
Radiation therapy (Radiation Therapy, RT) is one of the most common therapeutic modalities for treating various localized solid cancers in human patients, in which X-rays, gamma rays, electrons, neutrons and charged particles induce cell damage either directly by interaction with critical targets or indirectly through free radicals (e.g. hydroxyl groups). However, radiation therapy damages both tumor cells and normal tissue cells, with major side effects. Thus, in this case, targeted therapy is developed, i.e. corresponding targeted therapeutic drugs are designed, and the targeted drugs enter the body to specifically select the carcinogenic sites to combine to act, so that tumor cells specifically die, and normal tissue cells around the tumor are not affected.
Although targeted therapies are effective in cancer treatment, resistance problems are often encountered due to tumor hypoxia present in almost all solid tumors. In an anoxic environment, free radicals, such as Reactive Oxygen Species (ROS), which can kill cancer, cannot be effectively generated, and thus, the anoxic effect seriously affects the therapeutic effect of radiation. In addition, anticancer gases are being used in local Tumor Microenvironments (TMEs), such as carbon monoxide (CO), hydrogen (H2), nitric Oxide (NO), and the like. Anticancer gases may exhibit a wider range of anticancer effects than other anticancer drugs due to their highly diffuse nature. NO is reported to promote cancer cell death through mitochondrial ROS signaling pathways. Increasing NO production in TME is, to some extent, beneficial for the treatment of various cancers. Conventional methods of NO delivery have primarily inhaled and orally absorbed NO donors, but often result in insufficient NO supply due to low circulating concentrations. The low yield of NO remains a challenging problem, and NO strategy is currently available to address this challenge.
Disclosure of Invention
In view of the above, the invention provides an anticancer prodrug, and also provides a preparation method of the anticancer prodrug, and the invention also provides an anticancer drug, so as to solve the problems of insufficient NO supply, poor targeting effect, incapability of controlling NO release and the like of the existing NO-type antitumor drug.
In a first aspect, the invention provides an anticancer prodrug comprising a platelet membrane derived vesicle (PM), PEG-modified gold nanoclusters (AuNCs-PEG), and Sodium Nitrosoferricyanide (SNP), said PEG-modified gold nanoclusters and sodium nitrosoferricyanide being encapsulated in said platelet membrane derived vesicle.
Preferably, the PEG-modified gold nanoclusters are Cy 5-PEG-SH-modified gold nanoclusters. In other embodiments, the PEG-modified gold nanoclusters may also be NH 2 -PEG-SH。
Preferably, the molecular weight of the Cy5-PEG-SH is 1-3 kDa. More preferably, the Cy5-PEG-SH has a molecular weight of 2kDa.
The anticancer prodrug (AuNCs-PEG-PM-SNP, APS) comprises a platelet membrane derivative vesicle, PEG modified gold nanoclusters and sodium nitrosoferricyanide, wherein the PEG modified gold nanoclusters and the sodium nitrosoferricyanide are coated in the platelet membrane derivative vesicle. The anticancer prodrug (AuNCs-PEG-PM-SNP, APS) has the following advantages: (1) Auncs-PEG-PM-SNP in the spokeHigh levels of anti-cancer Nitric Oxide (NO) are released by the reaction of SNP (sodium nitrosoferricyanide) with L-GSH (glutathione) under irradiation, and NO inhibits cellular respiration and O by down-regulating hypoxia factors 2 Consumption, O 2 The increase of the concentration promotes the effective generation of ROS in the tumor microenvironment to improve the radiotherapy effect, and the accurate medical treatment is realized through the process of releasing nitric oxide by light control. (2) AuNCs-PEG-PM-SNP (APS) has strong uptake capacity by tumor cells, can avoid organism immune system, smoothly enter cancer cells, and exert anti-tumor effect. (3) AuNCs-PEG-PM-SNP (APS) has various anticancer effects, and also includes: improve radiation therapy induced cancer cell death, NO induced specific cancer cell killing, inhibit stromal cell fraction in tumor microenvironment (tumor microenvironment, TME), destroy tumor growth. (4) AuNCs-PEG-PM-SNP (APS) can inhibit proliferation of tumor cells and enhance radiotherapy effect.
In a second aspect, the present invention also provides a method of preparing an anticancer prodrug comprising the steps of:
providing platelet membrane derived vesicles, PEG modified gold nanoclusters and sodium nitroferricyanide, mixing the platelet membrane derived vesicles, the PEG modified gold nanoclusters and the sodium nitroferricyanide, extruding the mixture through a porous membrane, centrifuging the extrudate, and collecting precipitate to obtain the anticancer prodrug.
Preferably, the platelet membrane derived vesicles are prepared by the following method:
providing a PBS suspension of platelets, freezing the PBS suspension below-70 ℃, thawing the PBS suspension of platelets at room temperature, centrifuging to collect precipitate, washing the precipitate with PBS mixed with protease inhibitor, transferring the precipitate into deionized water for water bath ultrasonic treatment, and extruding the solution after ultrasonic treatment through a porous membrane;
the power of the water bath ultrasonic wave is 70-150W, the time of the water bath ultrasonic wave is 3-10 min, and the aperture of the porous membrane is 50-500 nm.
Preferably, the PBS suspension of platelets is centrifuged at 4000g for 3min after thawing at room temperature to collect the precipitate, the power of the water bath ultrasound is 100W, and the time of the water bath ultrasound is 5min;
the solution after the ultrasonic treatment is extruded through a polycarbonate porous membrane with the thickness of 100nm and 200nm in sequence.
Preferably, the PEG modified gold nanoclusters are prepared by the following method:
providing PEG aqueous solution and gold nanocluster dispersion, stirring the gold nanocluster dispersion, and simultaneously dropwise adding the PEG aqueous solution into the gold nanocluster dispersion, and reacting for 1-5 h to prepare PEG modified gold nanoclusters;
one end of the PEG is sulfhydryl, the other end of the PEG is Cy5, and the concentration of the PEG aqueous solution is the same as that of the gold nanocluster dispersion.
Preferably, the mass ratio of the platelet membrane derived vesicles, the PEG-modified gold nanoclusters and the sodium nitrosoferricyanide is 1:1:10.
The preparation method of the anticancer prodrug has the advantages of simple steps, low cost, suitability for large-scale industrial production and the like.
In a third aspect, the present invention also provides an anticancer drug comprising the anticancer prodrug of the first aspect and pharmaceutically acceptable excipients. The anticancer drug has a plurality of advantages of the anticancer prodrug and can effectively improve the effect of radiotherapy.
Preferably, the anticancer drug is a tablet, an injection, a tincture, a suppository, a capsule, an ointment, an ophthalmic preparation, a pill, an implant, a syrup, an aerosol, a film, a granule, an oral solution, a powder, an ear preparation, a nasal preparation, a lotion, a liniment, a gel or a patch.
Advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the embodiments of the invention.
Drawings
For a clearer description of the present invention, reference will be made to the following detailed description of embodiments taken in conjunction with the accompanying drawings.
FIG. 1 is a TEM image of an APS according to one embodiment of the present invention;
FIG. 2 is a graph of UV-vis-NIR absorption spectra of the APS shown in FIG. 1;
FIG. 3 is a graph showing the diameter comparison of the materials prepared in example 1;
FIG. 4 is a graph showing the difference in substance versus O in cells 2 A consumption test result graph;
FIG. 5 is a graph showing the results of SNP and APS release of NO under various conditions;
FIG. 6 is a graph of sample uptake test results performed in RAW 264.7 at different concentrations;
FIG. 7 is a graph showing the results of sample uptake assays performed on CT26 cells at various concentrations;
FIG. 8 is a graph showing the results of clone survival analysis of CT26 cells.
Detailed Description
The following description is of the preferred embodiments of the present invention, and it should be noted that it will be apparent to those skilled in the art that modifications and variations can be made without departing from the principle of the invention, and these modifications and variations are also regarded as the scope of the invention.
In a first aspect, the invention provides an anticancer prodrug comprising a platelet membrane derived vesicle (PM), PEG-modified gold nanoclusters (AuNCs-PEG), and Sodium Nitrosoferricyanide (SNP), said PEG-modified gold nanoclusters and sodium nitrosoferricyanide being encapsulated in said platelet membrane derived vesicle.
Preferably, the PEG-modified gold nanoclusters are Cy 5-PEG-SH-modified gold nanoclusters.
Preferably, the molecular weight of the Cy5-PEG-SH is 1-3 kDa, more preferably, the molecular weight of the Cy5-PEG-SH is 2kDa.
In a second aspect, the present invention also provides a method of preparing an anticancer prodrug comprising the steps of:
providing platelet membrane derived vesicles, PEG modified gold nanoclusters and sodium nitroferricyanide, mixing the platelet membrane derived vesicles, the PEG modified gold nanoclusters and the sodium nitroferricyanide, extruding the mixture through a porous membrane, centrifuging the extrudate, and collecting precipitate to obtain the anticancer prodrug.
Preferably, the platelet membrane derived vesicles are prepared by the following method:
providing a PBS suspension of platelets, freezing the PBS suspension below-70 ℃, thawing the PBS suspension of platelets at room temperature, centrifuging to collect precipitate, washing the precipitate with PBS mixed with protease inhibitor, transferring the precipitate into deionized water for water bath ultrasonic treatment, and extruding the solution after ultrasonic treatment through a porous membrane;
the power of the water bath ultrasonic wave is 70-150W, the time of the water bath ultrasonic wave is 3-10 min, and the aperture of the porous membrane is 50-500 nm.
Preferably, the PBS suspension of platelets is centrifuged at 4000g for 3min after thawing at room temperature to collect the pellet.
Preferably, the power of the water bath ultrasonic wave is 100W, the frequency of the water bath ultrasonic wave is 53KHz, and the time of the water bath ultrasonic wave is 5min.
Preferably, the solution after ultrasound is extruded sequentially through a 100nm and 200nm polycarbonate porous membrane.
Preferably, the PEG modified gold nanoclusters are prepared by the following method:
providing PEG aqueous solution and gold nanocluster dispersion, stirring the gold nanocluster dispersion, simultaneously dropwise adding the PEG aqueous solution into the gold nanocluster dispersion, and reacting for 1-5 h to prepare PEG modified gold nanoclusters (AuNCs-PEG);
one end of the PEG is sulfhydryl, the other end of the PEG is Cy5, and the concentration of the PEG aqueous solution is the same as that of the gold nanocluster dispersion.
Preferably, the concentration of the PEG aqueous solution and the concentration of the gold nanocluster dispersion are both 1mg/ml.
Preferably, PEG aqueous solution is added dropwise into the gold nanocluster dispersion liquid and reacted for 2 hours, and the reacted dispersion system is washed twice in deionized water at 4 ℃.
Preferably, the mass ratio of the platelet membrane derived vesicles, the PEG-modified gold nanoclusters and the sodium nitrosoferricyanide is 1:1:10.
Preferably, the porous membrane is extruded through a 200nm polycarbonate porous membrane, and excess platelet membrane derived vesicles and sodium nitrosoferricyanide are removed by centrifugation to obtain the anticancer prodrug (AuNCs-PEG-PM-SNP).
In a third aspect, the present invention also provides an anticancer drug comprising the anticancer prodrug of the first aspect and pharmaceutically acceptable excipients.
Preferably, the anticancer drug is a tablet, an injection, a tincture, a suppository, a capsule, an ointment, an ophthalmic preparation, a pill, an implant, a syrup, an aerosol, a film, a granule, an oral solution, a powder, an ear preparation, a nasal preparation, a lotion, a liniment, a gel or a patch.
The preparation method of the anticancer prodrug and the prepared anticancer prodrug are described in detail below by specific examples.
Example 1
Preparation of platelet membrane derived vesicles (PM):
(1) Platelets (PLT) from C57BL/6 whole blood were isolated by gradient centrifugation. Specifically: 10mL of whole mouse blood was centrifuged at 100 Xg for 20 minutes without braking, and then the supernatant was further centrifuged at 800 Xg for 20 minutes to obtain platelets. The platelets obtained were washed with PBS and centrifuged several times for use.
(2) Aliquots of the PLT suspension were frozen in a-80℃refrigerator, then transferred to room temperature for thawing, and the pellet was collected by centrifugation at 4000 Xg for 3 minutes. The precipitated platelet membrane-derived vesicles (PM) were washed 3 times with PBS mixed with protease inhibitor tablets and transferred to deionized water, sonicated in capped glass vials using a water bath sonicator at 53kHz and 100W for 5 minutes, and finally extruded sequentially on a mini-extruder of 100nm and 200nm polycarbonate porous membranes to give platelet membrane-derived vesicles.
Preparation of PEG-modified gold nanoclusters (AuNCs-PEG)
1ml of an aqueous solution of Cy5-PEG-SH (average molecular weight: 2 kDa) at a concentration of 1mg/ml and 1ml of an AuNCs dispersion at a concentration of 1mg/ml were taken, and the aqueous solution of Cy5-PEG-SH was added dropwise to the AuNCs dispersion with vigorous stirring and reacted for 2 hours. The reacted dispersion was washed twice in deionized water at 4 ℃ to form PEG-modified nanocomposite (AuNCs-PEG).
Preparation of anticancer prodrug (AuNCs-PEG-PM-SNP, APS)
1ml of PBS solution containing 200. Mu.g of PEG-modified gold nanoclusters (AuNCs-PEG), 2mg of Sodium Nitrosoferricyanide (SNP) and 200. Mu.g of platelet membrane-derived vesicles (PM) were mixed, and the mixture of the previous steps was extruded 11 times through a 200nm polycarbonate porous membrane using an Avanti mini-extruder, and excess PM and SNP were removed by centrifugation to obtain APS. The freshly prepared APS was left overnight in 1 XPBS buffer at 4℃for further use.
Example 2
Example 2 differs from example 1 only in that: in the step of preparing the platelet membrane derived vesicle (PM), the frequency of water bath ultrasonic is 40kHz, the power of water bath ultrasonic is 150W, the time of water bath ultrasonic is 10 minutes, and finally the platelet membrane derived vesicle is obtained by extruding twice on a small extruder of a 200-nanometer polycarbonate porous membrane.
Example 3
Example 3 differs from example 1 in that: the mass ratio of the platelet membrane derived vesicles to the PEG-modified gold nanoclusters to the nitrosoferricyanide is 1:1:5.
Effect examples:
the following test was performed using the anticancer prodrug (AuNCs-PEG-PM-SNP, APS) prepared in example 1 as a sample.
As shown in FIG. 1, a TEM image of the anticancer prodrug AuNCs-PEG-PM-SNP (APS) in example 1 is shown. FIG. 1 shows that the diameter of SNP, auNCs-PEG loaded nanoparticles (APS) is about 100nm. As shown in fig. 2 (four curves from top to bottom at 400nm wavelength correspond to APS, SNP, auNCs and SH-PEG-Cy5, respectively), the UV-vis-NIR absorption spectrum of the APS prepared in example 1 is the sum of the absorption spectra of SNP, SH-PEG-Cy5, and APS, and the presence of SNP loading and PM coating in the anticancer prodrug was verified by UV-vis-NIR absorption spectrum. As shown in FIG. 3, which is a comparative plot of the diameters of PM, auNCs-PEG, and APS, APS (110.+ -. 3.6 nm) is slightly larger than AuNCs-PEG NP (100.+ -. 5.6 nm), indicating that the NP is encapsulated into PM.
Based on NO decomposition and O 2 Bubble generation the present invention further verifies the catalase-like nature of SNPs. As shown in FIG. 4 (25 min, from top to bottom)Four curves corresponding to Control group, aps+cell group, cell group and ap+cell group) in order, O in cells 2 Is consumed and then decreases by about 50% after 25 minutes. The addition of AP (AuNCs-PEG-PM) does not alter O in cells 2 Consumption, but APS can reduce O 2 Residual O in cells after 25 minutes 2 About 75%. The aps+cell group increased by 50% compared to the normal Cell group (Cell) without APS. As shown in FIG. 5 (three curves corresponding to each of SNP+5mM GSH group, APS+5mM GSH group and APS group from top to bottom at 72 hours), NO was rapidly released from SNP and APS in the presence of L-Glutathione (GSH). It is thus shown that APS promotes NO release in the presence of GSH and reduces O 2 Is not limited.
FIG. 6 (three side-by-side groups: auNCs-PEG group, AP group and APS group, respectively), and FIG. 7 (three side-by-side groups: APS group, AP group and AuNCs-PEG group, respectively), are results of AuNCs-PEG, AP, APS nanoparticle uptake test performed in RAW 264.7 (mouse macrophage-like cell line) and CT26 (mouse colon cancer cell line) cells at different concentrations, respectively, and the APS group has the strongest uptake capacity than other groups in CT26 cell treatments at different concentrations. Most importantly, the uptake capacity of the APS group of CT26 cells was much higher than that of RAW 264.7 macrophage-like cells. These results indicate that APS nanoparticles can evade the immune system of organisms, smoothly enter cancer cells, and exert targeted antitumor effects.
FIG. 8 shows the results of clone survival analysis of CT26 cells, wherein the rightmost end of the four curves corresponds to Control group, auNCs-PEG group, AP group and APS group in order from top to bottom, and the APS group is the group with the most obvious inhibition of tumor cell proliferation.
In summary, the anticancer prodrug APS of the present invention can not only inhibit proliferation of tumor cells, but also enhance the effect of radiotherapy.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (2)

1. An anticancer prodrug is characterized by comprising a platelet membrane derived vesicle, PEG modified gold nanoclusters and sodium nitrosoferricyanide, wherein the PEG modified gold nanoclusters and the sodium nitrosoferricyanide are coated in the platelet membrane derived vesicle;
the PEG modified gold nanoclusters are Cy5-PEG-SH modified gold nanoclusters;
the molecular weight of the Cy5-PEG-SH is 1-3 kDa;
the preparation method of the anticancer prodrug comprises the following steps:
providing platelet membrane derived vesicles, PEG modified gold nanoclusters and sodium nitroferricyanide, mixing the platelet membrane derived vesicles, the PEG modified gold nanoclusters and the sodium nitroferricyanide, extruding the mixture through a porous membrane, centrifuging the extrudate, and collecting precipitate to obtain an anticancer prodrug;
the platelet membrane derived vesicles are prepared by the following method:
providing a PBS suspension of platelets, freezing the PBS suspension below-70 ℃, thawing the PBS suspension of platelets at room temperature, centrifuging to collect precipitate, washing the precipitate with PBS mixed with protease inhibitor, transferring the precipitate into deionized water for water bath ultrasonic treatment, and extruding the solution after ultrasonic treatment through a porous membrane;
the power of the water bath ultrasonic wave is 70-150W, the time of the water bath ultrasonic wave is 3-10 min, and the aperture of the porous membrane is 50-500 nm;
centrifuging the PBS suspension of the platelets for 3min at 4000g after thawing at room temperature to collect precipitate, wherein the power of water bath ultrasonic treatment is 100W, and the time of water bath ultrasonic treatment is 5min;
extruding the solution after ultrasonic treatment through a polycarbonate porous membrane with the thickness of 100nm and 200nm in sequence;
the PEG modified gold nanoclusters are prepared by the following method:
providing PEG aqueous solution and gold nanocluster dispersion, stirring the gold nanocluster dispersion, and simultaneously dropwise adding the PEG aqueous solution into the gold nanocluster dispersion, and reacting for 1-5 h to prepare PEG modified gold nanoclusters;
one end of the PEG is sulfhydryl, the other end of the PEG is Cy5, and the concentration of the PEG aqueous solution is the same as that of the gold nanocluster dispersion;
the mass ratio of the platelet membrane derived vesicles to the PEG-modified gold nanoclusters to the nitrosoferricyanide is 1:1:10.
2. An anticancer drug, which is characterized by comprising the anticancer prodrug of claim 1 and pharmaceutically acceptable auxiliary materials;
the anticancer drug is in the form of tablet, injection, tincture, suppository, capsule, ointment, ophthalmic preparation, pill, implant, syrup, aerosol, membrane, granule, oral solution, powder, ear preparation, nasal preparation, lotion, liniment, gel or patch.
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尹恩华 编著.NO前体药.《气体信息分子与生命科学》.天津科学技术出版社,2018,第393-394页. *

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