Tumor cell-derived drug-loaded vesicle and temperature-sensitive nanogel composition as well as preparation method and application of tumor cell-derived drug-loaded vesicle and temperature-sensitive nanogel composition

Abstract

The invention discloses a tumor cell-derived drug-loaded vesicle and temperature-sensitive nanogel composition and a preparation method and application thereof, and belongs to the technical field of tumor treatment, and the composition comprises a poly-N-isopropylacrylamide-butyl methacrylate nanogel, iohexol and a drug-loaded vesicle. According to the tumor cell-derived drug-loaded vesicle and temperature-sensitive nanogel composition as well as the preparation method and the application thereof, the bioavailability of Dug (at) MPs is improved, the bioavailability of non-target visceral organs is reduced, the intra-tumor penetration distance of the drug is increased, precise cooperation of chemotherapy and interventional embolism treatment is realized, and the curative effect of the drug is improved. The medicine is far better than interventional embolism therapy or conventional interventional embolism chemotherapy, and recurrence and metastasis of tumors are effectively inhibited.

Description

Technical Field

[0001] This invention relates to the field of tumor treatment technology, and in particular to a drug-loaded vesicle and thermosensitive nanogel composition derived from tumor cells, its preparation method and application. Background Technology

[0002] With the increasing incidence of cancer, transarterial chemoembolization (TACE) is the preferred treatment for advanced liver cancer. Embolizing agents play a crucial role in TACE therapy, not only blocking the nutrients necessary for tumor growth but also acting as drug delivery carriers. Currently, there are many commercially available embolizing agents, which can be classified into liquid and solid embolizing agents. Liquid embolizing agents mainly include iodized oil, alcohol, and gels, while solid embolizing agents mainly include traditional mechanical coils, PVA particles or microspheres, gelatin sponge particles, PLGA (polylactic-co-glycolic acid) microspheres, starch microspheres, and sodium alginate microspheres. However, some problems still exist with embolizing agents used clinically for tumor vessels. For example, iodized oil has low embolic strength and poor drug release ability; microspheres and particulate embolizing agents can cause catheter blockage and fail to reach small tumor vessels. These problems can ultimately lead to tumor recurrence and metastasis.

[0003] Exosomes (EVs) are nano / micron membrane vesicles secreted by almost all eukaryotic and prokaryotic cells. Based on their formation mechanism and typical size, EVs can be classified into exosomes, microvesicles (MVs or MPs), and apoptotic bodies. Exosomes are vesicles with a diameter of 30–150 nm, formed by inward budding of multivesicle bodies (MVBs), and released into the extracellular space when the MVBs fuse with the plasma membrane. MVs or MPs range in diameter from 50 nm to 1000 nm and are released from the cell via direct budding outside the plasma membrane. Apoptotic bodies are tiny vesicles that are released from senescent or apoptotic cells primarily through outward bubbling of the plasma membrane. EVs inherently carry a variety of biological components, including proteins, lipids, and nucleic acids, and are closely involved in intercellular communication. Due to their nanoscale structure and ability to transport bioactive cargo between cells or tissues, EVs show great potential as drug delivery carriers. Compared to synthetic drug delivery systems such as liposomes, micelles, and polymer-based synthetic nanoparticles, EVs possess various inherent properties (such as tumor-targeting properties and interactions with the tumor matrix or tumor blood vessels), making them suitable for crossing biological barriers, including tissue barriers, cellular barriers, and intracellular barriers, to deliver drugs to tumors. Wang et al. constructed a Bi2Se3 nanodot and doxorubicin (DOX) co-delivery system (Bi2Se3 / DOX) using MP derived from mouse hepatocellular carcinoma H22 cells via electroporation. Porous silica nanoparticles (PSiNPs) efficiently induced autophagy in tumor cells and were extracellularized from them. The extracellularly secreted PSiNPs were encapsulated in exosomes (E-PSiNPs), and notably, this method increased exosome production by approximately 34-fold compared to naturally secreted exosomes. After efficient internalization into tumor cells, the E-PSiNPs were extracellularized and then reinternalized by neighboring tumor cells, thereby achieving increased tumor accumulation and tumor depth penetration. Although exosomal MP has higher tumor targeting efficiency and can accumulate more in tumor areas compared to synthetic drug delivery systems (exosomal MP has a tumor targeting efficiency of 7%, while synthetic drug delivery systems have a tumor targeting efficiency of 0.7%), it still requires multiple systemic administrations in practical applications. Exosomal MP is lost in the bloodstream by 93%, so it is still necessary to solve the problem of large-scale drug acquisition and clearance from non-tumor sites.

[0004] From the initial C-TACE, represented by iodized oil and gelatin sponge, to the current DC... Drug-eluting microsphere embolization (D-TACE), represented by [example of chemotherapeutic embolization], has always emphasized drug loading. Loading multiple chemotherapeutic drugs to achieve slow release locally within tumor vessels has been a central theme in the evolution of embolization agents. However, due to the abnormal extracellular matrix and high interstitial pressure of tumors, chemotherapeutic drugs are prevented from further penetrating the tumor tissue. They mainly accumulate around tumor vessels and cannot reach the solid tumor interior. This is considered one of the important reasons why the five-year survival rate of transurethral chemoembolization (TACE) is not fundamentally different from that of transurethral embolization therapy (TAE) alone. Summary of the Invention

[0005] The purpose of this invention is to provide a drug-loaded vesicle and thermosensitive nanogel composition derived from tumor cells, its preparation method and application, which improves the bioavailability of Drug@MPs, reduces the bioavailability of non-target organs, enhances the intratumoral penetration distance of the drug, and achieves precise synergy between chemotherapy and interventional embolization therapy, which is far superior to interventional embolization therapy or conventional interventional embolization chemotherapy, and effectively inhibits tumor recurrence and metastasis.

[0006] To achieve the above objectives, the present invention provides a drug-loaded vesicle and thermosensitive nanogel composition derived from tumor cells, the composition comprising poly-N-isopropylacrylamide-butyl methacrylate nanogel, iohexol and drug-loaded vesicles.

[0007] Furthermore, the tumor cells from which the drug-loaded vesicles originate include one of HepG2, SMMC-7721, Bel-7402, MHCC97, and Huh7.

[0008] Preferably, the drug in the drug-loaded vesicles includes one of the following: chemotherapy drugs, glycolysis inhibitors, tumor angiogenesis-targeted therapy drugs, monoclonal antibodies, and active substances.

[0009] Preferably, the chemotherapy drugs include one of doxorubicin, gemcitabine, cisplatin, oxaliplatin, and 5-fluorouracil;

[0010] The drugs in the drug-loaded vesicles include glycolysis inhibitors, which include one of 2-deoxyglucose, 3-bromopyruvate, and 6-aminonicotinamide.

[0011] Tumor angiogenesis-targeted therapy drugs include one of the following: angiogenic agents, anti-angiogenic agents, and coagulation agents;

[0012] Monoclonal antibodies include one of nivolumab, pembrolizumab, durvalumab, and atezolizumab;

[0013] The active substances include one of oncolytic viruses, oncolytic bacteria, and oncolytic peptides.

[0014] Preferably, the vascular disruptor includes one of combutstatin A4 and 5,6-dimethylxanthine-4-acetic acid;

[0015] Anti-angiogenic agents include one of bevacizumab, sorafenib, donafenib, lenvatinib, and apatinib;

[0016] Coagulation drugs include one of tissue factor and thrombin.

[0017] This invention also provides a method for preparing a drug-loaded vesicle and thermosensitive nanogel composition derived from tumor cells, comprising the following steps:

[0018] Step 1: After irradiating tumor cells with ultraviolet light, co-incubate them with drugs and obtain drug-loaded vesicles by ultracentrifugation;

[0019] Step 2: Poly-N-isopropylacrylamide-butyl methacrylate nanogel was prepared by emulsion polymerization. The poly-N-isopropylacrylamide-butyl methacrylate nanogel was mixed with iohexol to prepare PIBI composite gel.

[0020] Step 3: Blend the PIBI composite gel with drug-loaded vesicles to obtain the composition.

[0021] Preferably, in step one, the ratio of tumor cells to drug is: 0.1 mg to 5 mg of drug per 10 million tumor cells, the drug concentration is 1 to 2 mg / mL, the incubation time is 15 to 20 h, and the drug loading of the drug-loaded vesicles obtained by ultracentrifugation is 0.001 to 0.1 μg Drug / μg protein.

[0022] Preferably, in step one, the ultracentrifugation speed is 10,000-20,000 rpm and the time is 30-60 min.

[0023] Preferably, in step two, the mass ratio of poly-N-isopropylacrylamide-butyl methacrylate nanogel to iohexol is 1:(10-40).

[0024] Preferably, in step three, the amount of PIBI composite gel and drug-loaded vesicles used is: 1 mL of PIBI composite gel is used to add drug-loaded vesicles with a drug loading of 360-1080 μg, and the weight-volume percentage concentration of PIBI composite gel is 2-20%.

[0025] The present invention also provides an application of a tumor cell-derived drug-loaded vesicle and thermosensitive nanogel composition, wherein the above-described tumor cell-derived drug-loaded vesicle and thermosensitive nanogel composition is used in the preparation of a tumor treatment drug.

[0026] Furthermore, tumors include one of the following: liver cancer, kidney cancer, uterine fibroids, cervical cancer, nasopharyngeal angiofibroma, and paraganglioma.

[0027] Therefore, the present invention, employing the above-mentioned drug-loaded vesicles derived from tumor cells and thermosensitive nanogel composition, its preparation method, and its application, has the following beneficial effects:

[0028] (1) It overcomes the "fluidity-embolism dilemma" faced by commonly used embolic agents in clinical practice;

[0029] (2) The composition improves the bioavailability of drug-loaded vesicles (Drug@MPs) and reduces toxicity to non-target organs;

[0030] (3) The composition enhances the intratumoral penetration of the drug, thereby enhancing the therapeutic effect and inhibiting tumor recurrence and metastasis.

[0031] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0032] Figure 1 It is the PIB nanogel of Example 1 of this invention. 1 H-NMR spectrum;

[0033] Figure 2 This is a DLS image of the PIB nanogel from Example 1 of the present invention;

[0034] Figure 3 This is a Zeta potential diagram of the PIB nanogel in Example 1 of the present invention;

[0035] Figure 4 This is a TEM image of the PIB nanogel from Example 1 of the present invention;

[0036] Figure 5 This is a DLS diagram of the drug-loaded vesicles in Embodiment 1 of the present invention;

[0037] Figure 6 This is a Zeta potential diagram of the drug-loaded vesicles in Embodiment 1 of the present invention;

[0038] Figure 7 This is a TEM image of the drug-loaded vesicles of Embodiment 1 of the present invention;

[0039] Figure 8 This is a SEM image of PIBI-DOX@MPs from Embodiment 1 of the present invention;

[0040] Figure 9 This refers to the survival rate of PIBI-DOX@MPs and VX2 cells after co-incubation for 24 hours in Example 1 of this invention;

[0041] Figure 10 This describes the embolization status of PIBI-DOX@MPs in a decellularized liver model according to Example 1 of the present invention;

[0042] Figure 11 This is a schematic diagram of the animal experiment of PIBI-DOX@MPs in Embodiment 1 of the present invention;

[0043] Figure 12 This is a statistical chart of the average tumor growth of VX2 tumors in situ in New Zealand rabbits after different treatments according to the present invention.

[0044] Figure 13 This is a gross image of an in situ VX2 tumor in a New Zealand rabbit after different treatments, as described in Example 1 of this invention.

[0045] Figure 14 These are DSA images of tumor-feeding artery embolization before and after the embolization of the tumor in Embodiment 1 of the present invention. Detailed Implementation

[0046] The technical solution of the present invention will be further described below with reference to the accompanying drawings and embodiments.

[0047] Unless otherwise defined, the technical or scientific terms used in this invention shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0048] In this invention, unless otherwise specified, all other test materials and instruments are conventional test materials in the field and can be purchased through commercial channels.

[0049] Example 1

[0050] This invention provides a drug-loaded vesicle and thermosensitive nanogel composition derived from tumor cells, exhibiting good fluidity in vitro (25°C) and the ability to embolize blood vessels in vivo (37°C). The composition comprises poly-N-isopropylacrylamide-butyl methacrylate nanogel, iohexol, and drug-loaded vesicles. The preparation method of the composition includes the following steps:

[0051] Step 1: After irradiating VX2 cells with ultraviolet light, incubate them with DOX for 16 hours and obtain drug-loaded vesicles (DOX@MPs) by ultracentrifugation.

[0052] The ratio of VX2 cells to DOX was: 10 million tumor cells were incubated with 1 mg of DOX, and the ultracentrifugation speed was 14,000 rpm for 30 min. The drug loading of the drug-loaded vesicles obtained by ultracentrifugation was 0.0685 μg DOX / μg protein.

[0053] DLS diagram of drug-loaded vesicles as shown in Figure 1 Figure 5As shown, the average particle sizes of MPs and DOX@MPs are 532 nm and 501 nm, respectively.

[0054] Zeta point map of drug-loaded vesicles as follows Figure 6 As shown, the average Zeta potentials are -9.64 mV and -9.59 mV, respectively.

[0055] TEM image of drug-loaded vesicles as shown Figure 7 As shown, both MPs and DOX@MPs exhibit irregular, nearly circular cup-shaped structures.

[0056] Step 2: Poly-N-isopropylacrylamide-butyl methacrylate (PIB) nanogels were prepared by emulsion polymerization. The PIB nanogels were then mixed with iohexol to prepare the PIBI composite gel.

[0057] The PIBI composite gel was prepared using existing technology. The specific procedures will not be elaborated upon, but simply put: N-isopropylacrylamide (NIPAM, 20 mmol), butyl methacrylate (BMA, 1 mmol), N,N'-methylenebisacrylamide (MBA, 0.2 mmol), and sodium dodecyl sulfate (SDS, 0.5 mmol) were dissolved in 160 mL of ultrapure water. Under nitrogen protection, the reaction system was heated to 70 °C. Potassium persulfate (KPS, 0.35 mmol) was added as an initiator to initiate polymerization. After the reaction was complete, the mixture was dialyzed and lyophilized to obtain PIB nanogels. The PIB nanogels were then mixed with iohexol at a mass ratio of 1:10 to prepare the PIBI composite gel.

[0058] PIB nanogels 1 H-NMR spectrum as follows Figure 1 As shown, the specific data is as follows:

[0059] PIB: 1 H-NMR (600MHz, CDCl3) δ7.13–5.91(m,1H),4.25–3.66(m,1H),2.78–2.38(m,1.5H),2.35–1.51(m,2H),1.28–1.23(m,0.2H),1.24–0.76(m,5H).

[0060] DLS image of PIB nanogel as shown Figure 2 As shown, at 25°C, the average hydrated particle size of PIB nanogels is about 200 nm, while when the temperature rises to 37°C, the hydrated particle size of PIB nanogels shrinks to about 110 nm.

[0061] The zeta potential diagram of PIB nanogels is as follows: Figure 3As shown, the Zeta potential of PIB nanogel is approximately -1.78 mV at 25 °C and approximately -10.65 mV at 37 °C.

[0062] TEM image of PIB nanogel as shown Figure 4 As shown, at 25°C, the PIB nanogel appears as swollen black spheres with a particle size of approximately 200 nm; while at 37°C, the PIB nanogel appears as wrinkled gray spheres with a particle size of approximately 100 nm.

[0063] Step 3: Prepare a composition (PIBI-DOX@MPs) by blending 2.5% (w / v) PIBI composite gel with drug-loaded vesicles (DOX@MPs) at a mass ratio of 10:1.

[0064] SEM images of PIBI-DOX@MPs are shown below. Figure 8 As shown, PIBI-DOX@MPs exhibit a typical interconnected, irregular porous structure with a pore size of approximately 5 μm and a certain pore wall thickness; vesicle-like particles can also be observed adhering to the pore walls within PIBI-DOX@MPs.

[0065] Example 2

[0066] The difference between this embodiment and Embodiment 1 is that the drug in the drug-loaded vesicles in Embodiment 2 is 2-deoxyglucose, while all other conditions are the same.

[0067] Example 3

[0068] The difference between this embodiment and embodiment 1 is that the drug in the drug-loaded vesicles in embodiment 3 is nivolumab, while all other conditions are the same.

[0069] Example 4

[0070] The difference between this embodiment and embodiment 1 is that the drug in the drug-loaded vesicles in embodiment 4 is combutstatin A4, while all other conditions are the same.

[0071] Example 5

[0072] The difference between this embodiment and embodiment 1 is that the drug in the drug-loaded vesicles in embodiment 5 is an oncolytic virus, while all other conditions are the same.

[0073] 1. The drug release of PIBI-DOX@MPs obtained in Example 1 was tested:

[0074] The release of DOX@MPs from PIBI-DOX@MPs was studied using PBS with pH values ​​of 4.5, 6.5, and 7.4 as release media. The specific methods are as follows: PBS with different pH values ​​was preheated in a 37°C water bath. In a biosafety cabinet, 0.5 mL of PIBI-DOX@MPs was transferred into 15 mL sterile centrifuge tubes, the tubes were sealed, and the tubes were placed in a 37°C water bath for equilibration for 5 min. After the phase transition of PIBI-DOX@MPs, the tubes were quickly transferred to the biosafety cabinet, and 5 mL of preheated PBS with different pH values ​​was added to each tube. The tubes were immediately sealed and placed in a 37°C, 180 rpm shaker environment for release. At a given time point, 200 μL of the release solution was taken out, and 200 μL of preheated PBS with the same pH was added simultaneously. After the experiment, 100 μL of the release solution at each time point was taken, 1% SDS was added, the mixture was stirred evenly, and then sonicated for 10 min. After centrifugation at 14000 rpm for 30 min, the DOX concentration in the supernatant was detected by HPLC, and the release rate of DOX@MPs was calculated based on the DOX content. In PBS at pH 7.4, the cumulative release of DOX@MPs in PIBI-DOX@MPs over 7 days was 51.84 wt.%, while the cumulative release of DOX@MPs over 7 days was 55.97 wt.% at pH 6.5 and 68.82 wt.% at pH 4.5.

[0075] 2. Study on the cytotoxicity of PIBI-DOX@MPs prepared in Example 1 against tumor cells:

[0076] VX2 cells were seeded at a density of 1×10⁴ cells / well in 96-well plates and cultured overnight. After incubation, the culture medium was removed, and 100 μL of serum-free DMEM medium containing DOX, DOX@MPs, or DOX@MPs-Released (DOX concentration 1 μg / mL) was added to each group of cells. Cell-free serum-free medium was used as a blank control, and cell-containing, drug-free medium was used as a negative control. After incubation for 24 h, 10 μL of CCK-8 solution was added to each well, and incubation continued for another 4 h. The absorbance (OD value) of each well was then measured using a multi-mode microplate reader at 450 nm, and cell viability was calculated using the following formula:

[0077]

[0078] ODs, ODb, and ODn represent the OD values ​​of the drug-treated sample, blank control, and negative control, respectively. Simultaneously, the cell death of VX2 cells treated with DOX, DOX@MPs, or DOX@MPs-Rleased was detected using a live / dead cell double staining kit. Inverted fluorescence microscopy imaging results and quantitative results are shown below. Figure 9 As shown, the results indicated that all drugs effectively killed tumor cells, but the proportion of dead cells was higher in the DOX@MPs and DOX@MPs-Released treatment groups. Quantitative results showed that the proportion of dead cells in both the DOX@MPs and DOX@MPs-Released treatment groups was higher than that in the DOX-treated group. These results suggest that DOX@MPs-Released retains the tumor cell-killing toxicity of DOX@MPs, and its tumor cell-killing effect is superior to that of free DOX.

[0079] 3. Investigate the in vitro embolization effect of PIBI-DOX@MPs prepared in Example 1:

[0080] First, a cleared, decellularized liver was obtained through a decellularization process. Using Lipiodol-DOX, Lipiodol-DOX@MPs, and PIBI-DOX as controls, the decellularized liver was injected via the portal vein, and the results were observed under a stereomicroscope. Figure 10 As shown, Figure 10 The results showed that PIBI-DOX and PIBI-DOX@MPs could reach the vascular terminals and uniformly fill the entire vessel, which is beneficial for achieving stepwise cast embolization and sustained drug release. While Lipiodol-DOX and Lipiodol-DOX@MPs could also reach the vascular terminals, the drug they carried was not evenly distributed in the emulsion; the drug concentrated in larger vessels and diffused rapidly into the surrounding matrix, resulting in poor sustained drug release. This indicates that PIBI-DOX@MPs can form a cast distribution in decellularized liver vessels, and also demonstrates that PIBI is an excellent drug carrier with better drug delivery and sustained release effects.

[0081] 4. To investigate the antitumor effect of PIBI-DOX@MPs prepared in Example 1 on the New Zealand rabbit orthotopic VX2 tumor model:

[0082] like Figure 11 , Figure 13 As shown, tumor masses were in situ inoculated onto the livers of New Zealand rabbits. After the tumors grew to a certain size, transarterial chemoembolization (TACE) was performed. PBS, Lipiodol-DOX@MPs, PIBI, and PIBI-DOX were used as controls. DSA imaging before and after tumor-feeding artery embolization is shown in the figure. Figure 14 As shown, a clear tumor blood supply network was visible before embolization; 10 minutes after embolization, in the Lipiodol-DOX@MPs, PIBI, PIBI-DOX, and PIBI-DOX@MPs groups, the contrast agent could not image the tumor vessels (including fine peripheral vessels), indicating that these four materials successfully embolized tumor vessels at all levels. Figure 12As shown, after 14 days of TACE treatment, tumor growth was significantly slowed in the Lipiodol-DOX@MPs, PIBI, PIBI-DOX, and PIBI-DOX@MPs groups, indicating that TACE treatment with each material could inhibit tumor growth. The tumor-suppressing effects of the PIBI-DOX and PIBI-DOX@MPs groups were better than those of the PIBI group. This was due to the combined effects of chemotherapy and embolization. Among all groups, PIBI-DOX@MPs showed the best tumor-suppressing effect, which is the result of the synergistic effect of PIBI's excellent vascular embolization ability and DOX@MPs' good tumor penetration and killing ability.

[0083] Therefore, the present invention utilizes the above-mentioned tumor cell-derived drug-loaded vesicles and thermosensitive nanogel composition, its preparation method and application, which improves the bioavailability of Drug@MPs, reduces the bioavailability of non-target organs, enhances the intratumoral penetration distance of the drug, and achieves precise synergy between chemotherapy and interventional embolization therapy, which is far superior to interventional embolization therapy or conventional interventional embolization chemotherapy, and effectively inhibits tumor recurrence and metastasis.

[0084] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A composition of drug-loaded vesicles derived from tumor cells and thermosensitive nanogels, characterized in that: The composition includes poly-N-isopropylacrylamide-butyl methacrylate nanogel, iohexol, and drug-loaded vesicles.

2. The drug-loaded vesicles and thermosensitive nanogel composition derived from tumor cells according to claim 1, characterized in that: The drugs in the drug-loaded vesicles include one of the following: chemotherapy drugs, glycolysis inhibitors, tumor angiogenesis-targeted therapy drugs, monoclonal antibodies, and active substances.

3. The drug-loaded vesicles and thermosensitive nanogel composition derived from tumor cells according to claim 2, characterized in that: Chemotherapy drugs include one of the following: doxorubicin, gemcitabine, cisplatin, oxaliplatin, and 5-fluorouracil; The drugs in the drug-loaded vesicles include glycolysis inhibitors, which include one of 2-deoxyglucose, 3-bromopyruvate, and 6-aminonicotinamide. Tumor angiogenesis-targeted therapy drugs include one of the following: angiogenic agents, anti-angiogenic agents, and coagulation agents; Monoclonal antibodies include one of nivolumab, pembrolizumab, durvalumab, and atezolizumab; The active substances include one of oncolytic viruses, oncolytic bacteria, and oncolytic peptides.

4. The drug-loaded vesicles and thermosensitive nanogel composition derived from tumor cells according to claim 3, characterized in that: Vascular disruptors include one of combutstatin A4 and 5,6-dimethylxanthine-4-acetic acid; Anti-angiogenic agents include one of bevacizumab, sorafenib, donafenib, lenvatinib, and apatinib; Coagulation drugs include one of tissue factor and thrombin.

5. A method for preparing a drug-loaded vesicle and thermosensitive nanogel composition derived from tumor cells as described in any one of claims 1-4, characterized in that: Includes the following steps: Step 1: After irradiating tumor cells with ultraviolet light, co-incubate them with drugs and obtain drug-loaded vesicles by ultracentrifugation; Step 2: Poly-N-isopropylacrylamide-butyl methacrylate nanogel was prepared by emulsion polymerization. The poly-N-isopropylacrylamide-butyl methacrylate nanogel was mixed with iohexol to prepare PIBI composite gel. Step 3: Blend the PIBI composite gel with drug-loaded vesicles to obtain the composition.

6. The method for preparing a drug-loaded vesicle and thermosensitive nanogel composition derived from tumor cells according to claim 5, characterized in that: In step one, the ratio of tumor cells to drug is as follows: 0.1 mg to 5 mg of drug is incubated for every 10 million tumor cells, the drug concentration is 1-2 mg / mL, the incubation time is 15-20 h, and the drug loading of the drug-loaded vesicles obtained by ultracentrifugation is 0.001-0.1 μg Drug / μg protein.

7. The method for preparing a drug-loaded vesicle and thermosensitive nanogel composition derived from tumor cells according to claim 5, characterized in that: In step one, the ultracentrifugation speed is 10,000-20,000 rpm, and the time is 30-60 minutes.

8. The method for preparing a drug-loaded vesicle and thermosensitive nanogel composition derived from tumor cells according to claim 5, characterized in that: In step two, the mass ratio of poly-N-isopropylacrylamide-butyl methacrylate nanogel to iohexol is 1:(10-40).

9. The method for preparing a drug-loaded vesicle and thermosensitive nanogel composition derived from tumor cells according to claim 5, characterized in that: In step three, the amount of PIBI composite gel and drug-loaded vesicles used is as follows: 1 mL of PIBI composite gel is used to add drug-loaded vesicles with a drug loading of 360-1080 μg, and the weight-volume percentage concentration of PIBI composite gel is 2-20%.

10. The application of a drug-loaded vesicle derived from tumor cells and a thermosensitive nanogel composition, characterized in that: The drug-loaded vesicles derived from tumor cells and the thermosensitive nanogel composition according to any one of claims 1-4 are used in the preparation of drugs for treating tumors.

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