CN219208188U - Antitumor targeted nano-drug delivery controlled release system based on photodynamic driving cytoplasmic membrane activation - Google Patents
Antitumor targeted nano-drug delivery controlled release system based on photodynamic driving cytoplasmic membrane activation Download PDFInfo
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Abstract
The utility model discloses an anti-tumor targeted nano drug delivery controlled release system based on photodynamic driving cytoplasmic membrane activation, and relates to the technical field of drug delivery controlled release systems. The system comprises a hydrophilic coating layer, wherein the inside of the hydrophilic coating layer is coated with a lipophilic photosensitizer, a lipophilic medicament is combined on the lipophilic photosensitizer, and the outside of the hydrophilic coating layer is connected with a hydrophilic polyethylene glycol chain. The nano-drug delivery system can improve the solubility of the drug, greatly prolong the acting time of the drug, greatly increase the tumor distribution and bioavailability of the drug, improve the biological safety of the system, and simultaneously guide the anti-tumor treatment process through fluorescence imaging. The utility model solves the problems of lack of immunogenicity and insufficient subsequent anti-tumor immune activation of tumors in the prior art.
Description
Technical Field
The utility model relates to the technical field of drug delivery controlled release systems, in particular to an anti-tumor targeted nano drug delivery controlled release system based on photodynamic driving cytoplasmic membrane activation.
Background
With the continued development of immunotherapeutic drugs, immunotherapy has also become an effective treatment regimen for cancer following surgery, chemotherapy and radiation therapy. In recent years, tumor immunotherapy typified by immune checkpoint blockade (Immune checkpoint blockade, ICB) has been shown to have excellent therapeutic effects in the treatment of various solid tumors such as non-small cell lung cancer, liver cancer, melanoma, and esophageal cancer. However, tumour immunotherapy still faces serious challenges, especially the abnormally low response rate of most solid tumours to immunotherapy, where the lack of immunogenicity and subsequent insufficient anti-tumour immune activation of the tumour are key causes.
ICB drugs are combined with treatment modes such as chemotherapy, targeted therapy, photodynamic therapy (Photodynamic therapy, PDT) and the like, and by means of other treatment modes, the response rate of ICB drugs is expected to be enhanced by reducing tumor load and improving tumor immunogenicity, and meanwhile, the synergistic anti-tumor effect of different treatment mechanisms is exerted, so that a good tumor treatment effect is finally shown. The nanometer drug delivery systems such as micelle, liposome, polymer nanometer particles and the like can integrate various anticancer treatment methods, realize co-delivery of combined drugs, improve tumor immunogenicity, excite T cell related immune response and obtain remarkable synergistic antitumor curative effect. The nano system can improve in vivo distribution and pharmacokinetic properties of the combined drug, effectively control the dosage and the acting time of the drug, improve the stability of the drug, reduce the toxic and side effects of the drug, further enhance the synergistic treatment effect, and provide a promising delivery strategy for the combination of ICB treatment and other treatment modes.
Disclosure of Invention
In order to solve the technical problems, the utility model aims to provide an anti-tumor targeted nano drug delivery controlled release system based on photodynamic driven cytoplasmic membrane activation, so as to solve the problems of lack of immunogenicity and insufficient subsequent anti-tumor immune activation of tumors in the prior art.
The technical scheme for solving the technical problems is as follows: the anti-tumor targeting nano drug delivery controlled release system based on photodynamic driving cytoplasmic membrane activation comprises a hydrophilic wrapping layer, wherein a lipophilic photosensitizer is wrapped in the hydrophilic wrapping layer, a lipophilic drug is combined on the lipophilic photosensitizer, and a hydrophilic polyethylene glycol chain is connected to the outer part of the hydrophilic wrapping layer.
The utility model has the beneficial effects that: the nano-drug delivery system can improve the solubility of the drug, greatly prolong the acting time of the drug, greatly increase the tumor distribution and bioavailability of the drug, improve the biological safety of the system, and simultaneously guide the anti-tumor treatment process through fluorescence imaging.
Based on the technical scheme, the utility model can also be improved as follows:
further, the hydrophilic coating is an acetylated chondroitin sulfate polymeric system.
Further, the lipophilic photosensitizer is chlorin e6.
Further, the lipophilic drug is dihydroartemisinin.
Further, the hydrophilic polyethylene glycol chain is carboxylated methoxy polyethylene glycol 2000.
Further, the acetylated chondroitin sulfate polymerization system is prepared by the following method:
(2.1) dispersing chondroitin sulfate in an organic solvent, then adding pyridine and acetic anhydride, and stirring at room temperature for reaction for 20-25h;
(2.2) transferring the reacted solution into a dialysis bag with a molecular weight cut-off of 800-1200D, dialyzing with deionized water, and freeze-drying to obtain AC-CS, i.e. an acetylated chondroitin sulfate polymerization system.
Further, in the step (2.1), the mass-volume ratio of the chondroitin sulfate to the organic solvent is 4-5mg:2-3mL.
Further, in the step (2.1), the volume ratio of pyridine, acetic anhydride and organic solvent is 0.03-0.05:0.02-0.03:20-30.
Further, in step (2.1), the organic solvent is formamide.
Further, in the step (2.2), the molecular weight cut-off was 1000D.
Further, in the step (2.2), the dialysis is performed for 3 to 5 days. Further, the structural formula of the acetylated chondroitin sulfate polymerization system is as follows:
further, carboxylated methoxypolyethylene glycol 2000 is prepared by the following method: (1.1) mixing mPEG2000, succinic anhydride and dimethylaminopyridine, dissolving the obtained mixture in chloroform, and reacting at 65 ℃ for 45-50 hours to prepare a reaction solution; (1.2) the reaction solution obtained in the step (1) is sequentially filtered, purified and dried to obtain mPEG2000-COOH, namely carboxylated methoxypolyethylene glycol 2000. Further, in the step (1.1), the mass ratio of mPEG2000, succinic anhydride and dimethylaminopyridine is 15-20:10-15:0.5-1. Further, in the step (1.1), the mass-volume ratio of the mixture to chloroform is 25-30g:200mL. Further, the carboxylated methoxypolyethylene glycol 2000 has the structural formula:
further, the anti-tumor targeted nano drug delivery controlled release system based on photodynamic driven cytoplasmic membrane activation is prepared by the following method: (1) Activating the carboxylated methoxy polyethylene glycol 2000 prepared in the step (1.2) by adopting N-hydroxysuccinimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to obtain a reactant I;
(2) Dispersing the acetylated chondroitin sulfate polymerization system prepared in the step (2.2) and 4-dimethylaminopyridine into dimethyl sulfoxide, adding the reactant I prepared in the step (1), reacting for 10-15 hours at room temperature, adding chlorin e6, reacting for 45-50 hours at room temperature, finally transferring into a dialysis bag with the molecular weight cutoff of 2500-3500D, dialyzing with deionized water, and freeze-drying to obtain mPEG-AC-CS-Ce6, namely methoxy polyethylene glycol 2000-acetylated chondroitin sulfate-chlorin e6;
(3) Dispersing dihydroartemisinin in dimethyl sulfoxide, dispersing in tetrahydrofuran, adding the mPEG-AC-CS-Ce6 and deionized water prepared in the step (2), carrying out ultrasonic mixing, transferring to a dialysis bag with the molecular weight cut-off of 800-1200D, dialyzing with deionized water, and freeze-drying to obtain the DHA@mPEG-AC-CS-Ce6, namely the antitumor targeted nano drug delivery controlled release system based on photodynamic driving cytoplasmic membrane activation.
Further, in the step (1), the mass ratio of carboxylated methoxypolyethylene glycol 2000, N-hydroxysuccinimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is 22 to 28:42-48:42-48.
Further, in the step (1), the mass ratio of carboxylated methoxypolyethylene glycol 2000, N-hydroxysuccinimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is 25:45:45.
further, in the step (2), the mass ratio of the acetylated chondroitin sulfate polymerization system, 4-dimethylaminopyridine and chlorin e6 is 50-60:80-90:10-20.
Further, in the step (2), the mass ratio of the acetylated chondroitin sulfate polymerization system, 4-dimethylaminopyridine and chlorin e6 is 55:85:15.
further, in the step (2), the mass ratio of the acetylated chondroitin sulfate polymerization system to the carboxylated methoxypolyethylene glycol 2000 is 50-60:22-28.
Further, in the step (2), the mass ratio of the acetylated chondroitin sulfate polymerization system to the carboxylated methoxypolyethylene glycol 2000 is 55:25.
further, in the step (3), the mass-volume ratio of the dihydroartemisinin, the dimethyl sulfoxide, the tetrahydrofuran, the mPEG-AC-CS-Ce6 and the deionized water is 0.8-1.2mg: 45-55. Mu.L: 4-6mL:4-6mg:8-11mL.
Further, in the step (3), the mass-volume ratio of the dihydroartemisinin, the dimethyl sulfoxide, the tetrahydrofuran, the mPEG-AC-CS-Ce6 and the deionized water is 1mg:50 μl:5mL:5mg:10mL.
Further, in the step (2), the molecular weight cut-off was 3000D.
Further, in the step (2), dialysis is performed for 3-5d.
Further, in the step (3), dialysis is performed for 3-5d.
Further, the structural formula of mPEG-AC-CS-Ce6 is as follows:
the utility model has the following beneficial effects:
1. PACC (mPEG-AC-CS-Ce 6) macromolecule nano-carrier has stronger conformation flexibility under the assistance of bulky hydrophilic PEG chain, so that the PACC (mPEG-AC-CS-Ce 6) macromolecule nano-carrier has excellent tumor cell membrane targeting affinity, and the PACC (mPEG-AC-CS-Ce 6) macromolecule nano-carrier has the capability of resisting cell uptake by uniquely selecting the steric hindrance of the hydrophilic PEG fragment, thus bringing good membrane targeting effect; meanwhile, a lipophilic Ce6 (chlorin e 6) molecule can be inserted on a phospholipid bilayer of a plasma membrane, and a targeting affinity exists between acetylated chondroitin sulfate (AC-CS) and a cell membrane CD44 receptor, so that the binding capacity of PACC molecules and the plasma membrane can be enhanced.
2. An acetylation reaction is induced to increase the solubility of the sodium chondroitin sulfate with strong hydrophilicity in a dimethyl sulfoxide solvent, so that the covalent grafting reaction of a photosensitizer chlorin e6 is promoted, and the yield of a final product is increased.
3. The sodium chondroitin sulfate, namely polysaccharide polymer with a large number of negative anions, is singly selected, and the chondroitin sulfate can prevent nanoparticles from agglomerating to form large particles due to the fact that the nanoparticles are electrostatically combined with anionic proteins in blood in the blood circulation process after intravenous injection, so that rapid metabolism by reticuloendothelial systems is prevented, and the half-life of the drug action is prolonged; the chondroitin sulfate can serve as a hydrophilic chain segment part of the polymer nano-particles, and also can play a role of a tumor cell targeting ligand, namely, the chondroitin sulfate has stronger affinity with CD44 protein overexpressed on the surface of a breast cancer cell membrane, so that the nano-preparation is promoted to be taken up by cancer cells.
4. The dihydro porphine e6 is exclusively selected as a photosensitizer, and the lipophilicity ensures that the dihydro porphine e6 can be grafted on a polysaccharide skeleton as a hydrophobic chain segment part, and can not only exert stable photodynamic conversion effect, but also serve as an autofluorescent agent to track the dynamic position of nano particles in-vitro cells or in-vivo tissues, so that the antitumor process is guided.
5. The unique selection of lipophilic dihydroartemisinin belongs to sesquiterpene lactone compounds containing peroxy bridging groups, and can be combined with chlorin e6 through hydrophobic acting force, so that the dihydroartemisinin is wrapped in nanoparticle cores. Meanwhile, the multifunctional nano preparation plays roles of a chemotherapeutic agent and an immunity inducer, and can generate a large number of free oxidation free radicals through Fe2+ mediated cleavage of peroxy bridge groups in dihydroartemisinin, so as to oxidize lipid, protein and DNA, and destroy cell membranes to cause a large number of extracellular substances to leak out, so that the multifunctional nano preparation can induce programmed death of tumor cells, promote the occurrence of death of immunogenic cells and further cause cell-specific anti-tumor immune response.
6. After being phagocytosed by breast cancer cells, most of fluorescence is positioned on cell membranes, so that tumor cell membranes can drive the nanoparticles to be assembled into a plurality of polymer molecules with chain segments opened in a non-covalent bond breaking mode through photodynamic, and plasma membrane positioning of photosensitizers is realized. Meanwhile, the carrier disassembly and assembly mode of tumor plasma membrane activation can also be used for controlling and releasing the carried medicine, thereby ensuring the effective exertion of the functions of the model medicine.
Drawings
FIG. 1 is DHA@mPEG-AC-CS-Ce6 prepared in example 1;
FIG. 2 is a flow chart of the self-assembly and disassembly process of DHA@mPEG-AC-CS-Ce6 prepared in example 1.
Wherein, 1, hydrophilic wrapping layer; 2. hydrophilic polyethylene glycol chains; 3. a lipophilic photosensitizer; 4. lipophilic drugs.
Detailed Description
The principles and features of the present utility model are described below with reference to the drawings, the examples are illustrated for the purpose of illustrating the utility model and are not to be construed as limiting the scope of the utility model.
In one embodiment of the utility model, as shown in fig. 1, an anti-tumor targeting nano-drug delivery controlled release system based on photodynamic driving cytoplasmic membrane activation is provided, and comprises a hydrophilic coating layer 1, wherein a lipophilic photosensitizer 3 is coated inside the hydrophilic coating layer, a lipophilic drug 4 is combined on the lipophilic photosensitizer, and a hydrophilic polyethylene glycol chain 2 is connected outside the hydrophilic coating layer.
In this embodiment, the preparation method of the antitumor targeted nano drug delivery controlled release system based on photodynamic driven cytoplasmic membrane activation comprises the following steps:
(1)mPEG2000-COOH
(1.1) mixing 16g of mPEG2000, 13g of succinic anhydride and 0.5g of dimethylaminopyridine, dissolving the obtained mixture in 200mL of chloroform subjected to drying treatment, reacting for 45-50h in an oil bath at 65 ℃, and condensing with condensed water to prepare a reaction solution;
(1.2) cooling the reaction solution prepared in the step (1) to room temperature, filtering with filter paper, removing the solvent by rotary evaporation, dissolving the residual white solid in 20mL of 1mol/L hydrochloric acid, extracting with chloroform, drying the organic phase with anhydrous sodium sulfate, filtering, precipitating the filtrate with diethyl ether, and drying in vacuum to obtain mPEG2000-COOH, namely carboxylated methoxypolyethylene glycol 2000;
the reaction equation is as follows:
(2)AC-CS
(2.1) dispersing 4.5mg of chondroitin sulfate in 2.5mL of formamide, quickly polymerizing and uniformly mixing, then adding 4 mu L of pyridine and 2.5 mu L of acetic anhydride, and stirring and reacting for 20-25h at room temperature;
(2.2) transferring the reacted solution into a dialysis bag with the molecular weight cut-off of 1000D, dialyzing with deionized water, and freeze-drying to obtain AC-CS, namely an acetylated chondroitin sulfate polymerization system;
the reaction equation is as follows:
(3) Controlled release system for nano drug delivery
(3.1) mixing the carboxylated methoxypolyethylene glycol 2000 (25 mg) obtained in step (1.2) with N-hydroxysuccinimide (45 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (45 mg), and then performing an activation treatment to obtain a first reactant;
(3.2) dispersing the acetylated chondroitin sulfate polymerization system (55 mg) and 4-dimethylaminopyridine (85 mg) prepared in the step (2.2) into dimethyl sulfoxide, then adding the reactant I prepared in the step (3.1), reacting for 12 hours at room temperature, adding chlorin e6 (15 mg), reacting for 48 hours at room temperature, finally transferring into a dialysis bag with a molecular weight cut-off of 3000D, dialyzing with deionized water, and freeze-drying to obtain mPEG-AC-CS-Ce6, namely methoxypolyethylene glycol 2000-acetylated chondroitin sulfate-chlorin e6;
(3.3) dispersing 1mg of dihydroartemisinin in dimethyl sulfoxide (50 mu L), then dispersing in 5mL of tetrahydrofuran, adding the mPEG-AC-CS-Ce6 (5 mg) prepared in the step (3.2) and deionized water (10 mL), carrying out ultrasonic mixing uniformly, transferring to a dialysis bag with the molecular weight cut-off of 1000D, dialyzing for 72h with deionized water, and freeze-drying to obtain the DHA@mPEG-AC-CS-Ce6, namely the antitumor targeted nano drug delivery controlled release system based on photodynamic driving cytoplasmic membrane activation.
The reaction equation is as follows:
the targeted nano-drug delivery controlled release system in this example disintegrates to release dihydroartemisinin as shown in figure 2. The DHA@mPEG-AC-CS-Ce6 prepared in the embodiment is irradiated by 660nm red light for 5min under the condition of 0.5W/cm < 2 > of power density, so that the DHA@mPEG-AC-CS-Ce6 is disintegrated, and dihydroartemisinin (the reaction formula is shown as follows) is released, the AC-CS-Ce6 has Reactive Oxygen Species (ROS) sensitivity, and ROS generated by the AC-CS-Ce6 micelle under the irradiation of 660nm can directly damage the chondroitin sulfate polysaccharide skeleton, so that the skeleton is degraded into oligosaccharide or monosaccharide. And (3) describing the accumulated release trend of the dihydroartemisinin DHA for the accumulated amount of the target DHA released from the drug-loaded nano-particles by using the characteristic ultraviolet absorption of the dihydroartemisinin at 300nm, which is obtained by ultraviolet UV-vis.
The foregoing description of the preferred embodiments of the utility model is not intended to limit the utility model to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the utility model are intended to be included within the scope of the utility model.
Claims (5)
1. The anti-tumor targeted nano drug delivery controlled release system based on photodynamic driving cytoplasmic membrane activation is characterized by comprising a hydrophilic coating layer (1), wherein a lipophilic photosensitizer (3) is coated inside the hydrophilic coating layer (1), a lipophilic drug (4) is combined on the lipophilic photosensitizer (3), and a hydrophilic polyethylene glycol chain (2) is connected outside the hydrophilic coating layer (1).
2. The photodynamic driven cytoplasmic membrane activation based anti-tumor targeted nano drug delivery controlled release system according to claim 1, wherein the hydrophilic coating (1) is an acetylated chondroitin sulfate polymeric system.
3. The photodynamic driven cytoplasmic membrane activation based anti-tumor targeted nano-drug delivery controlled release system according to claim 1, wherein the lipophilic photosensitizer (3) is chlorin e6.
4. The photodynamic driven cytoplasmic membrane activation based anti-tumor targeted nano-drug delivery controlled release system according to claim 1, wherein the lipophilic drug (4) is dihydroartemisinin.
5. The photodynamic driven cytoplasmic membrane activation based anti-tumor targeted nano drug delivery controlled release system according to claim 1, wherein the hydrophilic polyethylene glycol chain (2) is carboxylated methoxy polyethylene glycol 2000.
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| CN115554412A (en) * | 2022-11-01 | 2023-01-03 | 成都大学 | Plasma membrane anchored photodynamic polymer nano-carrier and preparation method and application thereof |
| CN115554412B (en) * | 2022-11-01 | 2024-07-05 | 成都大学 | Plasma membrane anchored photodynamic polymer nano-carrier and preparation method and application thereof |
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