Preparation and application of a kind of albumin-paclitaxel conjugate nanoparticle

Abstract

The application discloses a kind of albumin-paclitaxel twin drug nanoparticles and application, belong to the field of pharmaceutical chemistry and biopharmaceutical technology, specifically related to albumin is mixed with water, and albumin solution is prepared;Paclitaxel or paclitaxel twin drug compound is mixed with organic solvent, and drug solution is obtained;Albumin solution and drug solution are mixed, and after ultrasonic dispersion, spinning, ultrafiltration are carried out to prepare albumin binding type paclitaxel or albumin-paclitaxel twin drug nanoparticles.The albumin-paclitaxel twin drug prepared in the application can utilize the special GP60-cellar protein-SPARC transport mechanism of albumin, increase the accumulation of drug in tumor, and in vivo and in vitro experiments prove that the albumin-paclitaxel twin drug nanoparticles described in the application have good antitumor effect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicinal chemistry and biopharmaceutical technology, and particularly relates to a kind of albumin-paclitaxel twin drug nanoparticles and its preparation and application. BACKGROUND

[0002] Malignant tumor is a major global public health problem, and its incidence and mortality rate are increasing year by year, which seriously threatens human life safety. At present, chemotherapy is still the main means for treating malignant tumors (especially pancreatic cancer), but most anti-tumor drugs are severely limited in clinical transformation due to their low solubility, easy clearance by the body, lack of tumor-specific targeting, and other problems.

[0003] Albumin has good biocompatibility and water solubility, and its unique GP60-caveolin-SPARC transport mechanism can achieve tumor targeting and penetration, making it an ideal drug delivery carrier. In addition, simple physical methods such as ultrasound and stirring can be used to prepare uniform nanoparticles, which can enhance drug accumulation in tumor tissues through the EPR effect, and achieve the effect of enhancing the efficacy of the loaded drug and reducing its toxicity. In 2005, Abraxane (an albumin-bound paclitaxel nanoparticle complex) developed by American Celgene Corporation was approved for marketing by FDA, and has become the main chemotherapy drug for metastatic breast cancer, non-small cell lung cancer, pancreatic cancer and other malignant tumors.

[0004] Due to the metabolic abnormalities and complex microenvironment of tumors, the efficacy of single chemotherapy drug is often poor, and the development of multi-drug combination therapy is expected to bring new hope to patients. At present, the combination of Abraxane with carboplatin, gemcitabine and other anti-tumor drugs has become the first choice for the treatment of various cancers due to its good therapeutic effect. Although combination therapy can significantly improve the survival rate of patients, there are still many problems to be solved, such as low bioavailability, poor targeting, and obvious side effects of free drugs such as carboplatin and gemcitabine. In addition, the most difficult problem of combination therapy is the large difference in pharmacokinetics and pharmacodynamics of different drugs, the unclear in vivo efficacy, and the complex drug regimen, which seriously limits the development of multi-drug combination therapy. SUMMARY

[0005] In view of the above problems, we covalently linked paclitaxel to cytotoxic drugs, small molecule targeted drugs, immune checkpoint inhibitors, hormone drugs and immune agonists to construct a class of paclitaxel twin drugs, and then reacted with albumin to form uniform albumin-paclitaxel twin drug nanoparticle complexes, thereby achieving efficient co-loading of multiple drugs. Through targeted delivery, drug molecules are released in the tumor area, achieving the purpose of treating and regressing tumors. This technology is expected to break through the current efficacy bottleneck of malignant tumors.

[0006] The present application aims to provide a preparation and application of albumin-paclitaxel twin drug nanoparticles with good anti-proliferation, pro-killing, cancer cell metastasis prevention and stability.

[0007] The first object of the present application aims to provide a synthesis method of paclitaxel connecting with different anti-tumor drugs to form paclitaxel twin drugs, realizing efficient co-loading of multiple drugs and specific response release of the loaded drugs in tumor cells.

[0008] The second object of the present application aims to construct a series of uniform and stable albumin-paclitaxel twin drug nanoparticles by using albumin wrapping technology, and the nanoparticles include but are not limited to single drug, double drug and multiple drug forms.

[0009] The third object of the present application aims to provide and compare the anti-tumor effects of the above albumin-paclitaxel twin drug nanoparticles.

[0010] The paclitaxel twin drug of the present application is connected by covalent chemical bond between paclitaxel and anti-tumor drugs.

[0011] The technical scheme adopted by the present application to achieve the above objects is as follows:

[0012] A paclitaxel twin drug compound has the following structural formula:

[0013] , R is a drug molecule, including any one of cytotoxic drugs, small molecule targeted drugs, immune checkpoint inhibitors, hormone drugs and immune agonists; the structure of Linker is as follows: 、 、 、 、 、 、 and , wherein n is any integer from 1 to 14, m is any integer from 1 to 14, R1 is at least one of hydrazone bond, hydrazine bond, disulfide bond, thioether bond, diselenide bond, selenide bond, sulfur ketone bond and Michael adduct, R2 is at least one of hydrazone bond, hydrazine bond, disulfide bond, thioether bond, diselenide bond, selenide bond, sulfur ketone bond and Michael adduct, R3 is at least one of hydrazone bond, hydrazine bond, disulfide bond, thioether bond, diselenide bond, selenide bond, sulfur ketone bond and Michael adduct, and R4 is at least one of hydrazone bond, hydrazine bond, disulfide bond, thioether bond, diselenide bond, selenide bond, sulfur ketone bond and Michael adduct.

[0014] Preferably, the drug molecule is any one of T785, di-ABZI, SR07, Crizotinb, Palbociclib, MK1775, MK2206, AZD7762, Ceritinib, Navitoclax, Dasatinib and Exatecan; or, the structure of the Linker is as follows: .

[0015] The application discloses a preparation method of the paclitaxel twin drug compound.

[0016] Preferably, the Linker molecule is reacted with NpCl in a solvent to prepare an intermediate SS-2, then the SS-2 is reacted with PTX in dichloromethane to prepare PTX-SS-Np, and then the PTX-SS-Np is reacted with the drug molecule in DMF to prepare the paclitaxel twin drug compound. The Linker molecule is SS-1.

[0017] Preferably, a solvent is used in the combination reaction, and the solvent is one or more of dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, 1,4-dioxane, dimethyl sulfoxide, benzene, toluene, xylene, chlorobenzene and o-dichlorobenzene; or, an alkaline reagent is used in the combination reaction, and the alkaline reagent is one or more of alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal or alkaline earth metal carbonate, alkali metal or alkaline earth metal bicarbonate, triethylamine, tributylamine, trioctylamine, N,N-diisopropyl ethylamine, pyridine, 4-dimethylamino pyridine, piperidine, N-methyl morpholine, N-methyl piperidine, tetrahydro pyrrole, triethylene diamine and tetrabutyl ammonium hydroxide; or, a condensing agent is used in the combination reaction, and the condensing agent is one or more of EDCI, DCC and DIC.

[0018] The application discloses a paclitaxel twin drug nanoparticle, wherein the paclitaxel twin drug nanoparticle comprises the paclitaxel twin drug compound.

[0019] Preferably, the paclitaxel twin drug nanoparticle further comprises albumin, and the paclitaxel twin drug compound is bonded to the albumin.

[0020] More preferably, the albumin comprises at least one of bovine serum albumin, human serum albumin, ovalbumin and recombinant human serum albumin; or, the bonding is non-covalent bonding; or, the paclitaxel twin drug nanoparticle comprises at least one paclitaxel twin drug compound.

[0021] Preferably, the paclitaxel prodrug nanoparticles comprise one paclitaxel prodrug compound; or, the paclitaxel prodrug nanoparticles comprise two paclitaxel prodrug compounds; or, the paclitaxel prodrug nanoparticles comprise three paclitaxel prodrug compounds; or, the paclitaxel prodrug nanoparticles comprise four paclitaxel prodrug compounds; or, the paclitaxel prodrug nanoparticles comprise five paclitaxel prodrug compounds.

[0022] The application discloses a preparation method of paclitaxel prodrug nanoparticles, which comprises the following steps: mixing the paclitaxel prodrug compound and albumin in a complex solution to prepare paclitaxel prodrug nanoparticles.

[0023] Preferably, the paclitaxel prodrug compound is prepared into a drug solution in an organic solvent; the drug solution is mixed with an albumin solution to prepare a nanosuspension; and the organic solvent in the nanosuspension is evaporated and removed, and the nanosuspension is concentrated by ultrafiltration to obtain paclitaxel prodrug nanoparticles.

[0024] Preferably, the organic solvent comprises one or more of dichloromethane, chloroform, ethanol, DMSO, DMF and acetonitrile.

[0025] Preferably, the albumin solution is prepared by mixing albumin and water, and the concentration of albumin in the albumin solution is 1-100 mg / mL.

[0026] Preferably, an ultrasonic instrument is used in the nanosuspension, and the ultrasonic instrument comprises but is not limited to an ultrasonic crusher, an ultrasonic cleaning instrument and the like.

[0027] The application discloses the use of the paclitaxel prodrug compound in the preparation of a medicine for treating cancer, and the cancer comprises but is not limited to non-small cell lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, bladder cancer, breast cancer, lung cancer, gastric cancer and melanoma.

[0028] The application discloses the use of the paclitaxel prodrug nanoparticles in the preparation of a medicine for treating cancer, and the cancer comprises but is not limited to non-small cell lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, bladder cancer, breast cancer, lung cancer, gastric cancer and melanoma.

[0029] The preparation route of the paclitaxel prodrug compound is as shown in the following:

[0030] .

[0031] Preferably, in the preparation of the intermediate SS-2, DMAP is added into dichloromethane, NpCl and SS-1 are added under ice bath, stirring is carried out at 20-40 DEG C for 12-48 h, the reaction is monitored by TLC, after the reaction is completed, column chromatography is carried out to separate to obtain SS-2.

[0032] More preferably, in the preparation of the intermediate SS-2, the use amount of DMAP in dichloromethane is 2-8 g / mL.

[0033] More preferably, in the preparation of intermediate SS-2, the use of NpCl and dichloromethane is 5-20 g / mL.

[0034] More preferably, in the preparation of intermediate SS-2, the amount of SS-1 used is 20-30 wt% of NpCl.

[0035] Preferably, in the preparation of intermediate PTX-SS-Np, SS-2 is added to dichloromethane, then PTX and DIEA are added, stirring at 30-50°C for 5-24h, TLC monitoring the reaction, after the reaction is completed, column chromatography is used for separation to obtain PTX-SS-Np.

[0036] More preferably, in the preparation of intermediate PTX-SS-Np, the use of SS-2 and dichloromethane is 0.1-1 g / mL.

[0037] More preferably, in the preparation of intermediate PTX-SS-Np, the amount of PTX used is 40-80 wt% of SS-2.

[0038] More preferably, in the preparation of intermediate PTX-SS-Np, the use of DIEA and SS-2 is 0.1-0.5 mL / g.

[0039] Preferably, in the preparation of paclitaxel twin drug compounds, PTX-SS-Np is added to DMF, then the drug molecule and DIEA are mixed, stirring at 30-50°C for 5-24h, TLC monitoring the reaction, after the reaction is completed, column chromatography is used for separation to obtain paclitaxel twin drug compounds.

[0040] More preferably, in the preparation of paclitaxel twin drug compounds, the use of PTX-SS-Np and DMF is 0.05-0.5 g / mL.

[0041] More preferably, in the preparation of paclitaxel twin drug compounds, the amount of drug molecule used is 20-140 wt% of PTX-SS-Np.

[0042] More preferably, in the preparation of paclitaxel twin drug compounds, the use of DIEA and PTX-SS-Np is 0.2-1 mL / g.

[0043] Preferably, in the preparation of paclitaxel twin drug nanoparticles, paclitaxel twin drug compounds are added to chloroform, then ethanol is added to prepare a drug solution, the drug solution is mixed with an albumin solution to prepare a nanosuspension, the organic solvent in the nanosuspension is evaporated, and ultrafiltration is used for concentration to obtain paclitaxel twin drug nanoparticles.

[0044] More preferably, in the preparation of the paclitaxel twin drug nanoparticles, the paclitaxel twin drug compound is used in a relationship of 0.3-5 mg / μL with chloroform.

[0045] More preferably, in the preparation of the paclitaxel twin drug nanoparticles, the volume of ethanol used is 5-20% of the volume of chloroform used.

[0046] More preferably, in the preparation of the paclitaxel twin drug nanoparticles, the albumin solution is prepared by mixing albumin with water, and the concentration of albumin in the albumin solution is 1-10 mg / mL.

[0047] More preferably, in the preparation of the paclitaxel twin drug nanoparticles, when the drug solution is mixed with the albumin solution, the amount of drug solution used is based on the amount of chloroform used, and the volume of chloroform used is 1-10% of the volume of the albumin solution used.

[0048] The present application discloses a preparation method of albumin-paclitaxel twin drug nanoparticles, characterized in that it comprises the following steps:

[0049] S1, taking paclitaxel / paclitaxel twin drug dissolved in a mixture of organic solvents as a drug solution;

[0050] S2, preparing a specific concentration of albumin aqueous solution as an albumin solution;

[0051] S3, adding the drug solution to the albumin solution to prepare a nanosuspension by ultrasonic treatment;

[0052] S4, evaporating and removing the residual organic solvent in the nanosuspension obtained in step S3;

[0053] S5, concentrating the nanosuspension by ultrafiltration and storing it in a refrigerator.

[0054] Preferably, the drug solution in step S1 contains one or more of dichloromethane, chloroform, ethanol, DMSO, DMF, and acetonitrile; the concentration of albumin in the albumin solution in step S2 is 1-100 mg / mL; and the ultrasonic instrument used in step S3 includes but is not limited to an ultrasonic crusher and an ultrasonic cleaner.

[0055] When preparing the albumin-paclitaxel twin drug nanoparticles, two different drug solutions can be selected to be added to the albumin solution to prepare a nanosuspension by ultrasonic treatment, and then the subsequent steps are performed to prepare albumin-paclitaxel twin drug nanoparticles containing two drugs.

[0056] When preparing the albumin-paclitaxel twin drug nanoparticles, three different drug solutions can be selected to be added to the albumin solution to prepare a nanosuspension by ultrasonic treatment, and then the subsequent steps are performed to prepare albumin-paclitaxel twin drug nanoparticles containing three drugs.

[0057] After preparing paclitaxel twinned nanoparticles or albumin-paclitaxel twinned nanoparticles in this invention, the resulting nanoparticles can be configured for intravenous administration, oral administration, subcutaneous injection, or direct injection into or near tumors.

[0058] This invention discloses the preparation and application of albumin-bound paclitaxel nanoparticles (Nab-PTX).

[0059] This invention discloses the preparation and application of albumin-paclitaxel-derived twinned drug nanoparticles (Nab-pDCs).

[0060] Based on paclitaxel, this invention designs a class of paclitaxel twins that respond to stimulation of the tumor tissue microenvironment, enabling responsive release of antitumor drugs, reducing the toxic side effects of drugs on non-tumor cells, and thus improving efficacy.

[0061] This invention provides a series of methods for preparing paclitaxel twinned nanoparticles with albumin (e.g., human serum albumin) as the encapsulating carrier, comprising: preferably mixing human serum albumin with water to obtain an albumin solution; mixing paclitaxel or paclitaxel twinned nanoparticles with an organic solvent to obtain a drug solution; mixing the albumin solution and the drug solution, dispersing by ultrasonication, and then performing rotary evaporation and ultrafiltration to obtain albumin-bound paclitaxel or albumin-paclitaxel twinned nanoparticles.

[0062] In the technical solution disclosed in this invention, the aqueous solution of nanoparticles is stable at room temperature for at least 2 months or longer.

[0063] The drug-containing nanoparticles prepared by this invention have anti-tumor effects, including but not limited to anti-proliferation, promoting killing, and preventing cancer cell metastasis.

[0064] This invention employs a method of mixing albumin with water to obtain an albumin solution; mixing paclitaxel or a paclitaxel twin compound with an organic solvent to obtain a drug solution; and then mixing the albumin solution and the drug solution, followed by ultrasonic dispersion and rotary evaporation and ultrafiltration to obtain albumin-bound paclitaxel or albumin-paclitaxel twin drug nanoparticles. Therefore, it has the following beneficial effects: the albumin-paclitaxel twin drug prepared by this invention can utilize the unique GP60-SPARC transport mechanism of albumin to increase drug accumulation in tumors. In vitro and in vivo experiments have demonstrated that the albumin-paclitaxel twin drug nanoparticles of this invention have good anti-tumor effects. Therefore, this invention relates to the preparation and application of albumin-paclitaxel twin drug nanoparticles with anti-proliferation, cell killing, anti-metastasis, and good stability. Attached Figure Description

[0065] Figure 1 The particle size and surface potential diagram of albumin-paclitaxel twinned nanoparticles;

[0066] Figure 2 Cytotoxicity and combination index of paclitaxel in combination with antitumor drugs;

[0067] Figure 3 Figure showing the changes in tumor volume and body weight in C57 mice bearing pancreatic cancer after intravenous administration. Detailed Implementation

[0068] The technical solution of the present invention will be further described in detail below with reference to specific embodiments and accompanying drawings:

[0069] The synthetic route for the paclitaxel twin compound is shown below:

[0070] .

[0071] Example 1: Synthesis of intermediate SS-2

[0072] DMAP (3.6 g, 29.47 mmol) was weighed and dissolved in ultradry CH2Cl2 (100 mL). NpCl (12.0 g, 59.53 mmol) and SS-1 (3.0 g, 19.48 mmol) were slowly added under ice bath conditions, and the mixture was stirred (900 rpm) at room temperature for 24 hours. The reaction was monitored by TLC. After the reaction was completed, SS-2 (5.3 g, 56%) was obtained by column chromatography. 1 HNMR (400MHz, CDCl3) delta (ppm): 8.24 (d, J =10Hz, 4H), 7.36 (d, J =10Hz, 4H), 4.55 (t, J =4Hz, 4H), 3.08 (t, J =4Hz, 4H).

[0073] Example 2: Synthesis of intermediate PTX-SS-Np

[0074] SS-2 (4.0 g, 8.26 mmol) was weighed and dissolved in ultra-dry CH2Cl2 (10 mL). PTX (2.3 g, 2.69 mmol) and N,N-diisopropylethylamine (DIEA, 1.0 mL) were added, and the mixture was stirred at 40 °C (900 rpm) for 10 hours. The reaction was monitored by TLC. After the reaction was completed, PTX-SS-Np (2.1 g, 65.6%) was obtained by column chromatography. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.32-8.26 (m, 2H), 8.16-8.10 (d, ppm). J=8, 2H), 7.66-7.59 (m, 1H), 7.54-7.48 (m2H), 7.45-7.38 (m, 4H), 7.36-7.31 (m, 3H), 6.34-6.27 (br, 1H), 5.67-5.65 (d, J =4, 1H), 5.55-5.46 (m, 2H), 5.29 (s, 1H), 5.03-4.99 (d, J =8, 1H), 4.85 (s, 1H), 4.59-4.47 (m, 2H), 4.47-4.31 (m, 3H), 4.21-4.16 (m, 1H), 3.95-3.84 (m, 2H), 3.47 (s, 3H), 3.33 (s, 3H), 3.06-2.91 (m, 4H) , 2.77-2.67 (m, 1H), 2.47 (s, 3H), 2.35-2.20 (m, 2H), 2.03 (s, 3H), 1.85- 1.77 (m, 1H), 1.75 (s, 3H), 1.36 (s, 9H), 1.27 (s, 1H), 1.25-1.21 (m, 6H).

[0075] Example 3: Synthesis of PTX-SS-T785

[0076] PTX-SS-Np (200 mg, 0.17 mmol) was weighed and dissolved in ultra-dry DMF (2 mL). Then, compound T785 (0.2 mmol, 62.2 mg) and ultra-dry DIEA (100 μL) were added, mixed thoroughly, and stirred at 40 °C (900 rpm) for 10 hours. The reaction was monitored by TLC. After the reaction was completed, PTX-SS-T785 (165 mg, 72%) was obtained by column chromatography. 1 HNMR (600MHz, DMSO-) d 6) δ (ppm): 9.22 (d, J =8.5Hz, 1H), 8.42 (d, J =9.6Hz, 1H), 8.30 (s, 0H), 8.12–8.05 (m, 3H), 8.02–7.94 (m, 8H), 7.89–7.81 (m, 2H), 7.78–7. 67 (m, 3H), 7.68–7.51 (m, 11H), 7.51–7.38 (m, 15H), 7.29–7.11 (m, 7H), 6.42 (s, 5H), 6.30 (d, J =1.7Hz, 2H), 5.86 (dd, J =20.3, 10.0Hz, 2H), 5.58 (t, J=8.6Hz, 1H), 5.47–5.24 (m, 6H), 5.06–4.74 (m, 4H), 4.60 (d, J =10.6Hz, 2H), 4.49 (q, J =7.3Hz, 5H), 4.37 (td, J =6.1, 3.0Hz, 2H), 4.22 (t, J =6.5Hz, 2H), 4.12 (q, J =6.2Hz, 6H), 4.08–4.00 (m, 5H), 3.62 (dd, J =14.3, 7.2Hz, 3H), 3.11–2.96 (m, 7H), 2.94–2.81 (m, 9H), 2.41–2.30 (m, 1H), 2.27 (d, J =7.4Hz, 6H), 2.10 (d, J =1.3Hz, 6H), 1.84–1.69 (m, 6H), 1.73–1.39 (m, 19H), 1.24 (s, 6H), 1.11–0.99 (m, 14H), 0.95 (td, J =7.4, 3.8Hz, 6H). HR-MS (ESI): [PTX-SS-T785+H] + Theoretical value: 1371.5200, measured value m / z =1371.5141.

[0077] Example 4: Synthesis of PTX-SS-diABZI

[0078] PTX-SS-Np (100 mg, 0.083 mmol) was weighed and dissolved in ultra-dry DMF (2 mL). Then, compound di-ABZI (0.1 mmol, 77.9 mg) and ultra-dry DIEA (100 μL) were added and mixed thoroughly. The mixture was stirred at 40 °C (900 rpm) for 10 hours and the reaction was monitored by TLC. After the reaction was completed, PTX-SS-diABZI (60 mg, 39%) was obtained by column chromatography. 1 HNMR (400MHz, Chloroform- d ) δ8.17–8.03 (m, 2H), 8.00 (d, J =7.7Hz, 1H), 7.85 (d, J =7.8Hz, 1H), 7.68 (d, J =7.6Hz, 2H), 7.60–7.22 (m, 16H), 6.81 (d, J=35.0Hz, 4H), 6.71–6.54 (m, 2H), 6.22 (dd, J =26.6, 15.3Hz, 4H), 5.93 (dd, J =9.1, 3.7Hz, 1H), 5.74–5.25 (m, 8H), 5.06–4.73 (m, 6H), 4.58 (d, J =8.9Hz, 6H), 4.45–3.94 (m, 12H), 3.86–3.61 (m, 4H), 3.20 (s, 12H), 3.08–2.56 (m, 6H), 2 .58–2.05 (m, 12H), 2.02–1.50 (m, 12H), 1.47–1.30 (m, 8H), 1.31–1.11 (m, 16H), 1.08 (d, J =11.6Hz, 4H), 0.81 (t, J =7.0Hz, 3H). HR-MS (ESI): [PTX-SS-diABZI+H] + Theoretical value: 1839.6706, measured value m / z =1839.6501.

[0079] Example 5: Synthesis of PTX-SS-SR07

[0080] PTX-SS-Np (200 mg, 0.17 mmol) was weighed and dissolved in ultra-dry DMF (2 mL). Then, compound SR07 (0.2 mmol, 77.6 mg) and ultra-dry DIEA (100 μL) were added, mixed thoroughly, and stirred at 40 °C (900 rpm) for 10 hours. The reaction was monitored by TLC. After the reaction was completed, PTX-SS-SR07 (145 mg, 60%) was obtained by column chromatography. 1 HNMR (600MHz, DMSO-) d 6) δ13.00 (s, 1H), 9.22 (d, J =8.5Hz, 1H), 9.12 (d, J =8.7Hz, 0H), 8.89–8.78 (m, 2H), 8.55 (dd, J =9.1, 1.3Hz, 1H), 8.46 (d, J=9.1Hz, 1H), 8.26–8.18 (m, 2H), 8.10–7.93 (m, 2H), 7.89–7.81 (m, 2H), 7.78–7.68 (m, 1H) , 7.67–7.61 (m, 2H), 7.62–7.51 (m, 2H), 7.51–7.39 (m, 5H), 7.32–7.25 (m, 1H), 7.21 (ddt, J =6.4, 3.8, 2.0Hz, 1H), 6.30 (t, J =3.9Hz, 1H), 5.94–5.80 (m, 1H), 5.57 (td, J =8.6, 1.4Hz, 1H), 5.47–5.29 (m, 2H), 5.01–4.79 (m, 2H), 4.68–4.56 (m, 1H), 4.37 (t, J =5.3Hz, 3H), 4.33–3.92 (m, 6H), 3.60 (q, J =6.8, 6.2Hz, 1H), 3.45 (q, J =5.4Hz, 2H), 3.07–2.82 (m, 3H), 2.71–2.56 (m, 1H), 2.45–2.17 (m, 4H), 2.10 (t, J =2.1Hz, 3H), 1.94–1.74 (m, 4H), 1.70–1.53 (m, 2H), 1.50 (d, J =3.2Hz, 3H), 1.24 (s, 2H), 1.02 (dd, J =14.1, 3.5Hz, 6H). HR-MS (ESI): [PTX-SS-SR07+H] + Theoretical value: 1452.4135, measured value m / z =1452.4234.

[0081] Example 6: Synthesis of PTX-SS-Cri

[0082] PTX-SS-Np (200 mg, 0.17 mmol) was weighed and dissolved in ultra-dry DMF (2 mL). Then, Crizotinb (0.2 mmol, 89.8 mg) and ultra-dry DIEA (100 μL) were added, mixed thoroughly, and stirred at 40 °C (900 rpm) for 10 hours. The reaction was monitored by TLC. After the reaction was completed, PTX-SS-Crizotinb (228 mg, 90%) was obtained by column chromatography. 1 HNMR (600MHz, DMSO-) d 6) δ9.23 (d,J =8.5Hz, 1H), 8.44 (d, J =9.5Hz, 1H), 8.12–8.06 (m, 2H), 8.03–7.91 (m, 6H), 7.88–7.83 (m, 2H), 7.77–7.68 (m, 5H), 7.65 (t, J =7.7Hz, 2H), 7.63–7.52 (m, 10H), 7.52–7.38 (m, 13H), 7.22 (tt, J =6.5, 1.7Hz, 2H), 6.92 (t, J =2.0Hz, 2H), 6.31 (d, J =2.0Hz, 2H), 6.09 (qd, J =6.7, 2.1Hz, 2H), 5.93–5.82 (m, 2H), 5.68 (s, 4H), 5.59 (t, J =8.6Hz, 1H), 5.51–5.30 (m, 5H), 4.96–4.74 (m, 4H), 4.61 (d, J =11.6Hz, 2H), 4.44–4.18 (m, 8H), 4.17–3.93 (m, 10H), 3.70–3.57 (m, 3H), 3.11–2.92 (m, 9H), 2.90 (s, 1H), 2.81 (t, J =6.6Hz, 1H), 2.74 (s, 1H), 2.43–2.26 (m, 7H), 2.10 (d, J =3.0Hz, 6H), 2.05–1.97 (m, 5H), 1.91–1.78 (m, 14H), 1.75–1.63 (m, 2H), 1.58 (dd, J =15.3, 8.9Hz, 1H), 1.52 (d, J =1.7Hz, 6H), 1.25 (s, 6H), 1.13–0.94 (m, 12H). HR-MS (ESI): [PTX-SS-Cri+H] + Theoretical value: 1509.4275, measured value m / z =1509.4279.

[0083] Example 7: Synthesis of PTX-SS-Palb

[0084] PTX-SS-Np (200 mg, 0.17 mmol) was weighed and dissolved in ultra-dry DMF (2 mL). Then, Palbociclib (0.2 mmol, 89.5 mg) and ultra-dry DIEA (100 μL) were added, mixed thoroughly, and stirred at 40 °C (900 rpm) for 10 hours. The reaction was monitored by TLC. After the reaction was completed, PTX-SS-Palb (208 mg, 83%) was obtained by column chromatography. 1 HNMR (600MHz, DMSO-) d 6) δ10.02 (s, 1H), 9.23 (d, J =8.5Hz, 1H), 8.96 (d, J =1.3Hz, 1H), 8.13–8.04 (m, 1H), 8.03–7.94 (m, 2H), 7.92–7.84 (m, 3H), 7.78–7 .70 (m, 1H), 7.69–7.62 (m, 2H), 7.62–7.53 (m, 1H), 7.52–7.41 (m, 7H), 7.22 (tt, J =6.2, 2.3Hz, 1H), 6.31 (s, 1H), 5.97–5.76 (m, 2H), 5.59 (t, J =8.6Hz, 1H), 5.44 (d, J =7.1Hz, 1H), 5.40 (d, J =8.7Hz, 1H), 4.92 (dd, J =9.6, 2.2Hz, 1H), 4.84 (d, J =7.1Hz, 1H), 4.60 (s, 1H), 4.48–4.35 (m, 2H), 4.25 (t, J =6.1Hz, 2H), 4.13 (dt, J =11.1, 7.0Hz, 1H), 4.07–3.99 (m, 2H), 3.71–3.57 (m, 1H), 3.55 (t, J =5.2Hz, 5H), 3.25 (t, J =0.9Hz, 4H), 3.16 (t, J =5.3Hz, 5H), 3.08–2.93 (m, 4H), 2.43 (s, 3H), 2.32 (s, 3H), 2.27 (s, 2H), 2.11 (s, 2 H), 1.98–1.75 (m, 7H), 1.75–1.55 (m, 4H), 1.52 (s, 2H), 1.39–1.22 (m, 1H), 1.03 (d, J=15.4Hz, 6H). HR-MS (ESI): [PTX-SS-Palb+H] + Theoretical value: 1507.5473, measured value m / z =1507.5403.

[0085] Example 8: Synthesis of PTX-SS-MK1775

[0086] PTX-SS-Np (200 mg, 0.17 mmol) was weighed and dissolved in ultra-dry CH2Cl2 (3 mL). Then, compound MK1775 (0.17 mmol, 82.6 mg) and ultra-dry DIEA (100 μL) were added, mixed thoroughly, and stirred at 40 °C (900 rpm) for 10 hours. The reaction was monitored by TLC. After the reaction was completed, PTX-SS-MK1775 (146 mg, 55.7%) was obtained by column chromatography. 1 HNMR (600MHz, DMSO-) d 6) δ10.07 (s, 1H), 9.23 (d, J =8.5Hz, 0H), 8.83 (s, 1H), 8.44 (d, J =9.5Hz, 0H), 8.21–7.92 (m, 4H), 7.90–7.83 (m, 1H), 7.81–7.68 (m, 2H), 7.68–7.52 (m, 6H), 7.52–7.38 (m, 4H), 7.22 (dtd, J =6.4, 4.5, 4.1, 2.5Hz, 1H), 7.00–6.90 (m, 2H), 6.31 (s, 1H), 5.94–5.83 (m, 1H), 5.67 (ddt, J =17.2, 10.2, 6.0Hz, 1H), 5.59 (t, J =8.6Hz, 0H), 5.49–5.32 (m, 2H), 5.26 (s, 1H), 5.05–4.97 (m, 1H), 4.92 (dt, J =9.6, 2.1Hz, 1H), 4.89–4.82 (m, 2H), 4.68 (d, J =6.0Hz, 2H), 4.61 (d, J =12.1Hz, 1H), 4.40 (hept, J =6.3, 5.7Hz, 1H), 4.33–4.21 (m, 3H), 4.21–4.08 (m, 1H), 4.08–3.96 (m, 2H).

[0087] Example 9: Synthesis of PTX-SS-MK2206

[0088] PTX-SS-Np (200 mg, 0.17 mmol) was weighed and dissolved in ultra-dry DMF (2 mL). Then, compound MK2206 (0.2 mmol, 88.8 mg) and ultra-dry DIEA (100 μL) were added, mixed thoroughly, and stirred at 40 °C (900 rpm) for 12 hours. The reaction was monitored by TLC. After the reaction was completed, PTX-SS-MK2206 (120 mg, 50%) was obtained by column chromatography. 1 HNMR (600MHz, DMSO-) d 6) δ12.62 (s, 1H), 9.22 (d, J =8.5Hz, 1H), 8.36 (dd, J =5.7, 0.7Hz, 1H), 8.10–8.05 (m, 1H), 8.00 (dt, J =7.0, 1.4Hz, 1H), 7.96 (s, 2H), 7.94–7.83 (m, 3H), 7.76–7.68 (m, 1H), 7.68–7. 62 (m, 1H), 7.62–7.51 (m, 2H), 7.50–7.39 (m, 5H), 7.38–7.27 (m, 9H), 7.22 (ddd, J =8.4, 5.9, 3.1Hz, 1H), 6.96 (ddd, J =7.5, 4.1, 0.7Hz, 1H), 6.31 (d, J =2.4Hz, 1H), 5.96–5.79 (m, 1H), 5.59 (t, J =8.6Hz, 1H), 5.47–5.30 (m, 2H), 4.91 (dd, J =9.6, 2.2Hz, 1H), 4.84 (dd, J =11.1, 6.9Hz, 1H), 4.61 (d, J =9.5Hz, 1H), 4.45–4.34 (m, 1H), 4.34–4.18 (m, 1H), 4.18–3.92 (m, 5H), 3.62 (dd, J =13.6, 7.1Hz, 1H), 2.90 (d, J =0.5Hz, 10H), 2.74 (d, J =0.7Hz, 5H), 2.47–2.30 (m, 2H), 2.27 (d, J=6.4Hz, 3H), 2.15–2.07 (m, 3H), 2.05–1.92 (m, 0H), 1.91–1.75 (m, 4H), 1.65 (ddd, J =13.8, 11.0, 2.3Hz, 1H), 1.58 (dd, J =15.4, 9.0Hz, 0H), 1.55–1.47 (m, 3H), 1.30–1.22 (m, 1H), 1.12–0.94 (m, 6H). HR-MS (ESI): [PTX-SS-MK2206+H] + Theoretical value: 1467.4836, measured value m / z =1467.4476.

[0089] Example 10: Synthesis of PTX-SS-AZD7762

[0090] PTX-SS-Np (200 mg, 0.17 mmol) was weighed and dissolved in ultra-dry CH2Cl2 (3 mL). Then, compound AZD7762 (0.2 mmol, 72.4 mg) and ultra-dry DIEA (100 μL) were added, mixed thoroughly, and stirred at 40 °C (900 rpm) for 10 hours. The reaction was monitored by TLC. After the reaction was completed, PTX-SS-AZD (141 mg, 71%) was obtained by column chromatography. 1 HNMR (600MHz, DMSO-) d 6) δ11.75 (s, 1H), 9.06 (d, J =8.6Hz, 0H), 6.33 (s, 1H), 6.05–5.85 (m, 1H), 5.58–5.30 (m, 2H), 4.93 (dd, J =9.6, 2.3Hz, 1H), 4.75 (ddt, J =11.7, 7.5, 4.2Hz, 1H), 4.65 (d, J =6.6Hz, 1H), 4.47 (s, 1H), 4.43–3.88 (m, 8H), 3.81–3.70 (m, 1H), 3.66 (dd, J =7.3, 4.4Hz, 1H), 3.09–2.92 (m, 4H), 2.79–2.71 (m, 1H), 2.36 (ddd, J =14.3, 9.7, 6.6Hz, 1H), 2.29 (d, J =6.2Hz, 2H), 2.11 (d, J =2.8Hz, 3H), 1.84 (dd, J=11.5, 1.5Hz, 2H), 1.54 (s, 3H), 1.32–1.22 (m, 5H), 1.11–0.98 (m, 5H). HR-MS (ESI): [PTX-SS-AZD+H] + Theoretical value: 1422.4303, measured value m / z =1422.4294.

[0091] Example 11: Synthesis of PTX-SS-Cer

[0092] PTX-SS-Np (200 mg, 0.17 mmol) was weighed and dissolved in ultra-dry DMF (2 mL). Then, Ceritinib (0.187 mmol, 112 mg) and ultra-dry DIEA (100 μL) were added, mixed thoroughly, and stirred at 40 °C (900 rpm) for 10 hours. The reaction was monitored by TLC. After the reaction was completed, PTX-SS-Ceritinib (200 mg, 78%) was obtained by column chromatography. 1 HNMR (600MHz, DMSO-) d 6) δ9.46 (s, 1H), 9.23 (d, J =8.5Hz, 1H), 8.46 (d, J =8.4Hz, 1H), 8.25 (s, 1H), 8.02–7.91 (m, 3H), 7.85 (td, J =7.9, 1.4Hz, 3H), 7.79–7.70 (m, 1H), 7.69–7.60 (m, 2H), 7.58–7.53 (m, 1H), 7.52–7.41 (m, 5H), 7.36 (ddd, J =8.3, 7.4, 1.2Hz, 1H), 7.22 (ddd, J =6.2, 3.8, 2.5Hz, 1H), 6.82 (s, 1H), 6.31 (s, 1H), 6.13–5.78 (m, 1H), 5.59 (t, J =8.6Hz, 1H), 5.44 (d, J =7.1Hz, 1H), 5.39 (d, J =8.7Hz, 1H), 4.92 (dd, J =9.6, 2.3Hz, 1H), 4.66–4.49 (m, 2H), 4.40 (td, J =6.1, 4.7Hz, 1H), 4.24 (t, J =6.1Hz, 2H), 4.13 (dt, J=10.6, 6.6Hz, 3H), 4.03 (q, J =7.5, 6.8Hz, 2H), 3.61 (d, J =7.2Hz, 1H), 3.44 (p, J =6.8Hz, 1H), 3.11–2.82 (m, 6H), 2.45–2.31 (m, 1H), 2.27 (s, 3H), 2.21–2.07 (m, 6H), 1.93–1.81 (m, 4H), 1.74–1.63 (m, 3H), 1.57 (td, J =10.2, 8.8, 4.9Hz, 2H), 1.52 (s, 3H), 1.27–1.14 (m, 12H), 1.03 (d, J =15.5Hz, 6H). HR-MS (ESI): [PTX-SS-Cer+H] + Theoretical value: 1617.5762, measured value m / z =1617.5260.

[0093] Example 12: Synthesis of PTX-SS-Nav

[0094] PTX-SS-Np (200 mg, 0.17 mmol) was weighed and dissolved in ultra-dry DMF (2 mL). Then, Navitoclax (0.25 mmol, 243 mg) and ultra-dry DIEA (100 μL) were added, mixed thoroughly, and stirred at 40 °C (900 rpm) for 10 hours. The reaction was monitored by TLC. After the reaction was completed, PTX-SS-Navitoclax (121 mg, 35%) was obtained by column chromatography. 1 HNMR (600MHz, DMSO-) d 6) δ8.25 (s, 1H), 8.18 (d, J =2.2Hz, 1H), 8.09 (dt, J =8.4, 1.5Hz, 2H), 8.04–7.93 (m, 4H), 7.86 (dt, J =8.6, 1.6Hz, 0H), 7.78–7.67 (m, 5H), 7.66–7.51 (m, 4H), 7.51–7.39 (m, 5H), 7.40 –7.32 (m, 5H), 7.30–7.21 (m, 4H), 7.22–7.16 (m, 1H), 7.16–7.09 (m, 2H), 7.00 (dd, J =9.3, 4.4Hz, 1H), 6.89 (d, J =8.7Hz, 1H), 6.84 (d,J =8.9Hz, 2H), 6.33 (s, 1H), 6.03–5.89 (m, 1H), 5.70 (s, 2H), 5.47 (t, J =7.2Hz, 2H), 5.44–5.31 (m, 1H), 4.93 (dd, J =9.7, 2.3Hz, 1H), 4.65 (d, J =6.8Hz, 1H), 4.47 (s, 1H), 4.40 (t, J =6.2Hz, 0H), 4.38–4.13 (m, 7H), 4.11–4.01 (m, 4H), 3.66 (t, J =6.6Hz, 3H), 3.37–3.19 (m, 12H), 3.07–2.91 (m, 6H), 2.85 (t, J =6.4Hz, 1H), 2.80 (s, 3H), 2.40–2.15 (m, 20H), 2.11 (d, J =3.7Hz, 3H), 2.02 (d, J =2.3Hz, 3H), 1.99 (s, 1H), 1.85 (d, J =1.5Hz, 3H), 1.81–1.64 (m, 3H), 1.54 (s, 3H), 1.46 (t, J =6.5Hz, 3H), 1.34–1.23 (m, 14H), 1.20 (t, J =7.1Hz, 1H), 1.07 (d, J =3.7Hz, 7H), 0.99 (s, 7H), 0.88 (t, J =6.9Hz, 1H). HR-MS (ESI): [PTX-SS-Nav+H] + Theoretical value: 2032.6205, measured value m / z =2032.5682.

[0095] Example 13: Synthesis of PTX-SS-Das

[0096] PTX-SS-Np (200 mg, 0.17 mmol) was weighed and dissolved in ultra-dry DMF (2 mL). Then, Dasatinib (0.2 mmol, 88.7 mg) and ultra-dry DIEA (100 μL) were added, mixed thoroughly, and stirred at 40 °C (900 rpm) for 10 hours. The reaction was monitored by TLC. After the reaction was completed, PTX-L1-Dasatinib (101 mg, 39.6%) was obtained by column chromatography. 1HNMR (600MHz, DMSO-) d 6) δ11.87 (s, 1H), 11.44 (s, 5H), 9.83 (s, 5H), 9.23 (d, J =8.5Hz, 3H), 8.44 (d, J =9.6Hz, 2H), 8.22 (s, 5H), 8.14–8.06 (m, 5H), 8.04–7.95 (m, 11H), 7.91–7.84 (m, 5H), 7 .78–7.68 (m, 7H), 7.68–7.53 (m, 19H), 7.52–7.36 (m, 31H), 7.34–7.17 (m, 15H), 6.31 (d, J =1.0Hz, 5H), 6.08 (d, J =5.8Hz, 6H), 5.93–5.81 (m, 5H), 5.75 (s, 8H), 5.59 (t, J =8.6Hz, 2H), 5.47–5.29 (m, 13H), 4.92 (dt, J =9.6, 2.6Hz, 6H), 4.85 (dd, J =9.1, 6.9Hz, 5H), 4.61 (d, J =12.4Hz, 5H), 4.48–4.37 (m, 5H), 4.28–4.21 (m, 14H), 4.19–4.10 (m, 6H), 4.07–3.93 (m, 11H), 3.69–3.60 (m, 5H), 3.58–3.44 (m, 43H), 3.03 (d, J =6.2Hz, 4H), 2.99–2.92 (m, 13H). HR-MS (ESI): [PTX-SS-Das+H] + Theoretical value: 1548.4681, measured value m / z =1548.5617.

[0097] Example 14: Synthesis of PTX-SS-Exa

[0098] PTX-SS-Np (200 mg, 0.17 mmol) was weighed and dissolved in 2 mL of ultra-dry DMF. Then, Exatecan (0.2 mmol, 98.4 mg) and ultra-dry DIEA (100 μL) were added, mixed thoroughly, and stirred at 40 °C (900 rpm) for 10 hours. The reaction was monitored by TLC. After the reaction was completed, PTX-SS-Exatecan (228 mg, 90%) was obtained by column chromatography. 1 HNMR (600MHz, DMSO-)d 6) δ 9.23 (d, J J = 8.5 Hz, 1H), 8.42 (d, J J = 8.5 Hz, 2H), 8.12–8.06 (m, 1H), 8.02–7.98 (m, 2H), 7.97 (d, J J = 7.5 Hz, 1H), 7.90–7.83 (m, 2H), 7.80 (d, J J = 10.9 Hz, 1H), 7.76–7.70 (m, 1H), 7.65 (t, J J = 7.7 Hz, 2H), 7.62–7.52 (m, 2H), 7.52–7.39 (m, 7H), 7.33 (s, 2H), 7.22 (dq, J J = 8.7, 2.5 Hz, 1H), 6.45 (s, 1H), 6.31 (d, J J = 4.2 Hz, 1H), 5.90–5.81 (m, 1H), 5.64–5.51 (m, 3H), 5.47–5.35 (m, 5H), 5.31–5.12 (m, 3H), 4.92 (dt, J J = 9.8, 3.0 Hz, 1H), 4.84 (s, 2H), 4.61 (d, J J = 12.2 Hz, 1H), 4.39 (q, J J = 5.6 Hz, 2H), 4.14 (q, J J = 10.0, 8.2 Hz, 4H), 4.07–3.98 (m, 3H), 3.74–3.51 (m, 3H), 3.18 (d, J J = 5.5 Hz, 2H), 3.11–2.80 (m, 4H), 2.45–2.40 (m, 5H), 2.33 (dq, J J = 8.0, 3.4 Hz, 0H), 2.28 (d, J J = 8.8 Hz, 3H), 2.25–2.17 (m, 1H), 2.11 (d, J J = 1.0 Hz, 3H), 1.98–1.81 (m, 4H), 1.81 (d, J J = 1.4 Hz, 3H), 1.74–1.54 (m, 2H), 1.52 (d, J J = 2.4 Hz, 3H), 1.35–1.22 (m, 2H), 1.12–0.98 (m, 7H), 0.88 (t, J J = 7.3 Hz, 4H). HR-MS (ESI): [PTX-SS-Exa + H] + Theoretical value: 1552.4899, measured value m / z =1552.4907.

[0099] Example 15: Preparation of albumin-bound paclitaxel nanoparticles (Nab-PTX)

[0100] 1 mg of paclitaxel was dissolved in a mixture of 64.8 μL of chloroform and 7.2 μL of ethanol to form the organic phase. A 5 mg / mL human serum albumin aqueous solution was prepared to form the aqueous phase. 72 μL of the organic phase was added to 1 mL of the aqueous phase, and the mixture was sonicated continuously for 6 minutes using a 650 W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) with a 30-second sonication followed by a 15-second pause, to obtain a nano-suspension. Subsequently, the mixture was rotary evaporated for 30 minutes at 40 °C and 533 mbar vacuum control mode. Finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the nanoparticle complex.

[0101] Example 16: Preparation of albumin-PTX-SS-T785 nanoparticles

[0102] 1 mg of PTX-SS-T785 was weighed and dissolved in a mixture of 64.8 μL of chloroform and 7.2 μL of ethanol as the organic phase; a 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase; 72 μL of the organic phase was added to 1 mL of the aqueous phase, and the mixture was sonicated continuously for 6 minutes using a 650W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) with a program of 30 seconds of sonication followed by 15 seconds of pause, to obtain a nano-suspension; then, the mixture was rotary evaporated for 30 minutes using a rotary evaporator with a vacuum control mode of 40℃ and 533 mbar; finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the nanoparticle complex.

[0103] Example 17: Preparation of albumin-PTX-SS-di-ABZI nanoparticles:

[0104] 1 mg of PTX-SS-di-ABZI was weighed and dissolved in a mixture of 64.8 μL of chloroform and 7.2 μL of ethanol as the organic phase; a 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase; 72 μL of the organic phase was added to 1 mL of the aqueous phase, and the mixture was sonicated continuously for 6 minutes using a 650W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) with a program of 30 seconds of sonication followed by 15 seconds of pause, to obtain a nano-suspension; then, the mixture was rotary evaporated for 30 minutes using a rotary evaporator with a vacuum control mode of 40℃ and 533 mbar; finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the nanoparticle complex.

[0105] Example 18: Preparation of albumin-PTX-SS-SR07 nanoparticles:

[0106] 1 mg of PTX-SS-SR07 was dissolved in a mixture of 64.8 μL of chloroform and 7.2 μL of ethanol to form the organic phase. A 5 mg / mL human serum albumin aqueous solution was prepared to form the aqueous phase. 72 μL of the organic phase was added to 1 mL of the aqueous phase, and the mixture was sonicated continuously for 6 minutes using a 650 W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) with a 30-second sonication followed by a 15-second pause, to obtain a nano-suspension. Subsequently, the mixture was rotary evaporated for 30 minutes at 40 °C and 533 mbar vacuum control mode. Finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the nanoparticle complex.

[0107] Example 19: Preparation of albumin-PTX-SS-Cri nanoparticles:

[0108] 1 mg of PTX-SS-Crizotinib was dissolved in a mixture of 64.8 μL chloroform and 7.2 μL ethanol to form the organic phase. A 5 mg / mL human serum albumin aqueous solution was prepared to form the aqueous phase. 72 μL of the organic phase was added to 1 mL of the aqueous phase, and the mixture was sonicated continuously for 6 minutes using a 650 W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) with a 30-second sonication followed by a 15-second pause, to obtain a nano-suspension. Subsequently, the mixture was rotary evaporated for 30 minutes at 40 °C and 533 mbar vacuum control mode. Finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the nanoparticle complex.

[0109] Example 20: Preparation of albumin-PTX-SS-Palb nanoparticles

[0110] 1 mg of PTX-SS-Palbociclib was weighed and dissolved in a mixture of 64.8 μL of chloroform and 7.2 μL of ethanol as the organic phase; a 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase; 72 μL of the organic phase was added to 1 mL of the aqueous phase, and the mixture was sonicated continuously for 6 minutes using a 650W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) with a program of 30 seconds of sonication followed by 15 seconds of pause, to obtain a nano-suspension; then, the mixture was rotary evaporated for 30 minutes using a rotary evaporator with a vacuum control mode of 40℃ and 533 mbar; finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the nanoparticle complex.

[0111] Example 21: Preparation of albumin-PTX-SS-MK1775 nanoparticles

[0112] 1 mg of PTX-SS-MK1775 was weighed and dissolved in a mixture of 64.8 μL of chloroform and 7.2 μL of ethanol as the organic phase; a 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase; 72 μL of the organic phase was added to 1 mL of the aqueous phase, and the mixture was sonicated continuously for 6 minutes using a 650W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) with a program of 30 seconds of sonication followed by 15 seconds of pause, to obtain a nano-suspension; then, the mixture was rotary evaporated for 30 minutes using a rotary evaporator with a vacuum control mode of 40℃ and 533 mbar; finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the nanoparticle complex.

[0113] Example 22: Preparation of albumin-PTX-SS-MK2206 nanoparticles

[0114] 1 mg of PTX-SS-MK2206 was weighed and dissolved in a mixture of 64.8 μL of chloroform and 7.2 μL of ethanol as the organic phase; a 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase; 72 μL of the organic phase was added to 1 mL of the aqueous phase, and the mixture was sonicated continuously for 6 minutes using a 650W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) with a program of 30 seconds of sonication followed by 15 seconds of pause, to obtain a nano-suspension; then, the mixture was rotary evaporated for 30 minutes using a rotary evaporator with a vacuum control mode of 40℃ and 533 mbar; finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the nanoparticle complex.

[0115] Example 23: Preparation of albumin-PTX-SS-AZD nanoparticles

[0116] 1 mg of PTX-SS-AZD7762 was weighed and dissolved in a mixture of 64.8 μL of chloroform and 7.2 μL of ethanol as the organic phase; a 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase; 72 μL of the organic phase was added to 1 mL of the aqueous phase, and the mixture was sonicated continuously for 6 minutes using a 650W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) with a program of 30 seconds of sonication followed by 15 seconds of pause, to obtain a nano-suspension; then, the mixture was rotary evaporated for 30 minutes using a rotary evaporator with a vacuum control mode of 40℃ and 533 mbar; finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the nanoparticle complex.

[0117] Example 24: Preparation of albumin-Cer nanoparticles

[0118] 1 mg of PTX-SS-Ceritinib was dissolved in a mixture of 64.8 μL chloroform and 7.2 μL ethanol to form the organic phase. A 5 mg / mL human serum albumin aqueous solution was prepared to form the aqueous phase. 72 μL of the organic phase was added to 1 mL of the aqueous phase, and the mixture was sonicated continuously for 6 minutes using a 650 W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) with a 30-second sonication followed by a 15-second pause, to obtain a nano-suspension. Subsequently, the mixture was rotary evaporated for 30 minutes at 40 °C and 533 mbar vacuum control mode. Finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the nanoparticle complex.

[0119] Example 25: Preparation of albumin-PTX-SS-Nav nanoparticles

[0120] 1 mg of PTX-SS-Navitoclax was weighed and dissolved in a mixture of 64.8 μL of chloroform and 7.2 μL of ethanol as the organic phase; a 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase; 72 μL of the organic phase was added to 1 mL of the aqueous phase, and the mixture was sonicated continuously for 6 minutes using a 650W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) with a program of 30 seconds of sonication followed by 15 seconds of pause, to obtain a nano-suspension; then, the mixture was rotary evaporated for 30 minutes using a rotary evaporator with a vacuum control mode of 40℃ and 533 mbar; finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the nanoparticle complex.

[0121] Example 26: Preparation of albumin-PTX-SS-Das nanoparticles

[0122] 1 mg of PTX-SS-Dasatinib was dissolved in a mixture of 64.8 μL chloroform and 7.2 μL ethanol as the organic phase; a 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase; 72 μL of the organic phase was added to 1 mL of the aqueous phase, and the mixture was sonicated continuously for 6 minutes using a 650W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) with a program of 30 seconds of sonication followed by a 15-second pause, to obtain a nano-suspension; subsequently, the mixture was rotary evaporated for 30 minutes using a rotary evaporator at 40 °C and a vacuum control mode of 533 mbar; finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the nanoparticle complex.

[0123] Example 27: Preparation of albumin-PTX-SS-Exa nanoparticles

[0124] 1 mg of PTX-SS-Exatecan was dissolved in a mixture of 64.8 μL of chloroform and 7.2 μL of ethanol to form the organic phase. A 5 mg / mL human serum albumin aqueous solution was prepared to form the aqueous phase. 72 μL of the organic phase was added to 1 mL of the aqueous phase. The nano-suspension was obtained by continuous sonication for 6 minutes using a 650 W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) with a program of 30 seconds of sonication followed by a 15-second pause. The nano-suspension was then evaporated for 30 minutes using a rotary evaporator at 40 °C and a vacuum control mode of 533 mbar. Finally, the nanoparticle complex was obtained by ultrafiltration at 4000 rpm for 15 minutes using a 100 KD ultrafiltration tube.

[0125] Example 28: Preparation of albumin-PTX-SS-Cri@MK1775 nanoparticles

[0126] 0.5 mg of PTX-SS-Cri and PTX-SS-MK1775 were weighed and dissolved in a mixture of 32.4 μL chloroform and 3.6 μL ethanol to form organic phases A and B, respectively. A 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase. Organic phases A and B were added to 1 mL of the aqueous phase in a 1:1 ratio. A 650W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) was used to continuously sonicate for 6 minutes with a program of 30 seconds of sonication followed by a 15-second pause to obtain a nano-suspension. The nano-suspension was then rotary evaporated for 30 minutes at 40℃ and 533 mbar vacuum control mode. Finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the dual-drug nanoparticle complex.

[0127] Example 29: Preparation of albumin-PTX-SS-Exa@MK1775 nanoparticles

[0128] 0.5 mg of PTX-SS-Exa and PTX-SS-MK1775 were weighed and dissolved in a mixture of 32.4 μL chloroform and 3.6 μL ethanol to form organic phases A and B, respectively. A 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase. Organic phases A and B were added to 1 mL of the aqueous phase in a 1:1 ratio. A 650W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) was used to continuously sonicate for 6 minutes with a program of 30 seconds of sonication followed by a 15-second pause to obtain a nano-suspension. The nano-suspension was then rotary evaporated for 30 minutes at 40℃ and 533 mbar vacuum control mode. Finally, the nano-suspension was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the dual-drug nanoparticle complex.

[0129] Example 30: Preparation of albumin-PTX-SS-Pal@MK2206 nanoparticles

[0130] 0.5 mg of PTX-SS-Palbociclib and PTX-SS-MK2206 were weighed and dissolved in a mixture of 32.4 μL chloroform and 3.6 μL ethanol to form organic phases A and B, respectively. A 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase. Organic phases A and B were added to 1 mL of the aqueous phase in a 1:1 ratio. A 650W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) was used to continuously sonicate for 6 minutes with a program of 30 seconds of sonication followed by a 15-second pause to obtain a nano-suspension. The nano-suspension was then rotary evaporated for 30 minutes at 40℃ and 533 mbar vacuum control mode. Finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the dual-drug nanoparticle complex.

[0131] Example 31: Preparation of albumin-PTX-SS-MK2206@MK1775 nanoparticles

[0132] 0.5 mg of PTX-SS-MK2206 and PTX-SS-MK1775 were weighed and dissolved in a mixture of 32.4 μL chloroform and 3.6 μL ethanol to form organic phases A and B, respectively. A 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase. Organic phases A and B were added to 1 mL of the aqueous phase in a 1:1 ratio. A 650W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) was used to continuously sonicate for 6 minutes with a program of 30 seconds of sonication followed by a 15-second pause to obtain a nano-suspension. The nano-suspension was then rotary evaporated for 30 minutes at 40℃ and 533 mbar vacuum control mode. Finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the dual-drug nanoparticle complex.

[0133] Example 32: Preparation of albumin-PTX-SS-Das@MK1775 nanoparticles

[0134] 0.5 mg of PTX-SS-Dasatinib and PTX-SS-MK1775 were weighed and dissolved in a mixture of 32.4 μL chloroform and 3.6 μL ethanol to form organic phases A and B, respectively. A 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase. Organic phases A and B were added to 1 mL of the aqueous phase in a 1:1 ratio. A 650W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) was used to continuously sonicate for 6 minutes with a program of 30 seconds of sonication followed by a 15-second pause to obtain a nano-suspension. The nano-suspension was then rotary evaporated for 30 minutes at 40℃ and 533 mbar vacuum control mode. Finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the dual-drug nanoparticle complex.

[0135] Example 33: Preparation of albumin-PTX-SS-Exa@Cri nanoparticles

[0136] 0.5 mg of PTX-SS-Exatecan and PTX-SS-Crizotinib were weighed and dissolved in a mixture of 32.4 μL chloroform and 3.6 μL ethanol to form organic phases A and B, respectively. A 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase. Organic phases A and B were added to 1 mL of the aqueous phase in a 1:1 ratio. A 650W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) was used to continuously sonicate for 6 minutes with a program of 30 seconds of sonication followed by a 15-second pause to obtain a nano-suspension. The nano-suspension was then rotary evaporated for 30 minutes at 40℃ and 533 mbar vacuum control mode. Finally, the nanoparticles were ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the dual-drug nanoparticle complex.

[0137] Example 34: Preparation of albumin-PTX-SS-Exa@Das nanoparticles

[0138] 0.5 mg of PTX-SS-Exatecan and PTX-SS-Dasatinib were weighed and dissolved in a mixture of 32.4 μL chloroform and 3.6 μL ethanol to form organic phases A and B, respectively. A 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase. Organic phases A and B were added to 1 mL of the aqueous phase in a 1:1 ratio. A 650W probe ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) was used to continuously sonicate for 6 minutes with a program of 30 seconds of sonication followed by a 15-second pause to obtain a nano-suspension. The nano-suspension was then rotary evaporated for 30 minutes at 40℃ and 533 mbar vacuum control mode. Finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the dual-drug nanoparticle complex.

[0139] Example 35: Preparation of albumin-PTX-SS-MK2206@MK1775@T785 nanoparticles

[0140] 0.33 mg of PTX-SS-MK2206, PTX-SS-MK1775, and PTX-L-T785 were weighed and dissolved in a mixture of 21.6 μL chloroform and 2.4 μL ethanol to form three organic phases, A, B, and C, respectively. A 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase. The three organic phases A, B, and C were added to 1 mL of the aqueous phase in a 1:1:1 ratio. A 650W probe-type ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) was used to continuously sonicate for 6 minutes with a program of 30 seconds of sonication followed by a 15-second pause to obtain a nano-suspension. Subsequently, the nano-suspension was evaporated for 30 minutes on a rotary evaporator at 40℃ and 533 mbar vacuum control mode. Finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the three-drug nanoparticle complex.

[0141] Example 36: Preparation of albumin-PTX-SS-Cri@Cer@SR07 nanoparticles

[0142] 0.33 mg of PTX-SS-Crizotinib, PTX-SS-Ceritinib, and PTX-SS-SR07 were weighed and dissolved in a mixture of 21.6 μL chloroform and 2.4 μL ethanol to form three organic phases, A, B, and C, respectively. A 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase. The three organic phases A, B, and C were added to 1 mL of the aqueous phase in a 1:1:1 ratio. A 650 W probe-type ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) was used to continuously sonicate for 6 minutes with a program of 30 seconds of sonication followed by a 15-second pause to obtain a nano-suspension. Subsequently, the nano-suspension was evaporated for 30 minutes on a rotary evaporator at 40 °C and 533 mbar vacuum control mode. Finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the three-drug nanoparticle complex.

[0143] Example 37: Preparation of albumin-PTX-SS-MK2206@Pal@T785 nanoparticles

[0144] 0.33 mg of PTX-SS-MK2206, PTX-SS-Palbociclib, and PTX-SS-T785 were weighed and dissolved in a mixture of 21.6 μL chloroform and 2.4 μL ethanol to form three organic phases, A, B, and C, respectively. A 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase. The three organic phases A, B, and C were added to 1 mL of the aqueous phase in a 1:1:1 ratio. A 650W probe-type ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) was used to continuously sonicate for 6 minutes with a program of 30 seconds of sonication followed by a 15-second pause to obtain a nano-suspension. Subsequently, the nano-suspension was evaporated for 30 minutes on a rotary evaporator at 40℃ and 533 mbar vacuum control mode. Finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the three-drug nanoparticle complex.

[0145] Example 38: Preparation of albumin-PTX-SS-Pal@Cer@SR07 nanoparticles

[0146] 0.33 mg of PTX-SS-Palbociclib, PTX-SS-Ceritinib, and PTX-SS-SR07 were weighed and dissolved in a mixture of 21.6 μL chloroform and 2.4 μL ethanol to form three organic phases, A, B, and C, respectively. A 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase. The three organic phases A, B, and C were added to 1 mL of the aqueous phase in a 1:1:1 ratio. A 650 W probe-type ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) was used to continuously sonicate for 6 minutes with a program of 30 seconds of sonication followed by a 15-second pause to obtain a nano-suspension. Subsequently, the nano-suspension was evaporated for 30 minutes on a rotary evaporator at 40 °C and 533 mbar vacuum control mode. Finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the three-drug nanoparticle complex.

[0147] Example 39: Preparation of albumin-PTX-SS-Pal@Cer@T785 nanoparticles

[0148] 0.33 mg of PTX-SS-Palbociclib, PTX-SS-Ceritinib, and PTX-SS-T785 were weighed and dissolved in a mixture of 21.6 μL chloroform and 2.4 μL ethanol to form three organic phases, A, B, and C, respectively. A 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase. The three organic phases A, B, and C were added to 1 mL of the aqueous phase in a 1:1:1 ratio. A 650W probe-type ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) was used to continuously sonicate for 6 minutes with a program of 30 seconds of sonication followed by a 15-second pause to obtain a nano-suspension. Subsequently, the nano-suspension was evaporated for 30 minutes on a rotary evaporator at 40 °C and 533 mbar vacuum control mode. Finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the three-drug nanoparticle complex.

[0149] Example 40: Preparation of albumin-PTX-SS-Cer@Cri@T785 nanoparticles

[0150] 0.33 mg of PTX-SS-Ceritinib, PTX-SS-Crizotinib, and PTX-SS-T785 were weighed and dissolved in a mixture of 21.6 μL chloroform and 2.4 μL ethanol to form three organic phases, A, B, and C, respectively. A 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase. The three organic phases A, B, and C were added to 1 mL of the aqueous phase in a 1:1:1 ratio. A 650W probe-type ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) was used to continuously sonicate for 6 minutes with a program of 30 seconds of sonication followed by a 15-second pause to obtain a nano-suspension. Subsequently, the nano-suspension was evaporated for 30 minutes on a rotary evaporator at 40 °C and 533 mbar vacuum control mode. Finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the three-drug nanoparticle complex.

[0151] Example 41: Preparation of albumin-Exa@MK2206@SR07 nanoparticles

[0152] 0.33 mg of PTX-SS-Exatecan, PTX-SS-MK2206, and PTX-SS-SR07 were weighed and dissolved in a mixture of 21.6 μL chloroform and 2.4 μL ethanol to form three organic phases, A, B, and C, respectively. A 5 mg / mL human serum albumin aqueous solution was prepared as the aqueous phase. The three organic phases A, B, and C were added to 1 mL of the aqueous phase in a 1:1:1 ratio. A 650W probe-type ultrasonic disruptor (2 mm amplitude bar, 40% amplitude) was used to continuously sonicate for 6 minutes with a program of 30 seconds of sonication followed by a 15-second pause to obtain a nano-suspension. Subsequently, the nano-suspension was evaporated for 30 minutes on a rotary evaporator at 40℃ and 533 mbar vacuum control mode. Finally, it was ultrafiltered for 15 minutes at 4000 rpm using a 100 KD ultrafiltration tube to obtain the three-drug nanoparticle complex.

[0153] Experimental Example 1: Hydrated Particle Size and Surface Potential of Albumin-Based Paclitaxel-Derived Twin Drug Nanoparticles

[0154] The nanoparticles obtained in Examples 15-35 were diluted 10 times with deionized water, and the particle size and distribution and PDI of albumin-paclitaxel and albumin-paclitaxel twinned nanoparticles were determined using a Malvern Zetasizer Nano ZS nanoparticle size potentiometry instrument. Their surface potentials were also measured. The specific results are shown in Table 1.

[0155] Table 1. Test results of albumin-paclitaxel-derived twinned nanoparticles

[0156]

[0157] The results showed that, except for Nab-PTX with a hydrated particle size of 162.1 nm, the other albumin-bound paclitaxel-derived twins were all between 90 and 140 nm; the PDI was less than 0.24. The particle size and surface potential of the albumin-paclitaxel twin nanoparticles are as follows: Figure 1 As shown.

[0158] Experimental Example 2: Drug Loading Rate of Albumin-Based Paclitaxel-Derived Twin Drug Nanoparticles

[0159] Preferably, this study investigated the encapsulation efficiency and drug loading of PTX-SS-T785 in albumin-PTX-SS-T785 nanoparticles. 1.2 mg, 1.5 mg, and 2 mg of PTX-SS-T785 were weighed and dissolved in 1 mL of DMSO, respectively, and detected by high-performance liquid chromatography (HPLC) to create a standard curve. 1.4 mg of PTX-SS-T785 was weighed and albumin nanoparticles were prepared using the method described in Example 16. 12.5 μL of the sample was added to DMSO, sonicated for 10 minutes, and centrifuged at 8000 rpm for 5 minutes. The supernatant was collected, and the drug mass in the nanoparticles was measured. Then, 50 μL and 100 μL of the nanoparticles prepared using the method described in Example 16 were taken, and DMSO was added to a final volume of 500 μL. After sonication for 10 minutes, the mixture was centrifuged at 8000 rpm for 5 minutes, and the supernatant was injected into the HPLC for detection. The injection volume was 10 μL. Chromatographic conditions: A Waters XBridge-C18 column (4.6 × 250 mm, 5 μm) was used, with acetonitrile:water (65 / 35, v / v) as the mobile phase, a detection wavelength of 254 nm, and a column temperature of 40 °C. The drug encapsulation efficiency was calculated as follows, expressed as drug loading and encapsulation ratio:

[0160] Encapsulation efficiency (%) = (Material mass in nanoparticles / Actual dosage) × 100%;

[0161] Drug loading (%) = (Mass of drug in nanoparticles / Total mass of nanoparticles) × 100%;

[0162] The specific results are as follows: the total mass of albumin-PTX-SS-T785 nanoparticles is 19.433, the mass of PTX-L-T785 in the nanoparticles is 1 mg, and the encapsulation efficiency is 71.43% and the drug loading is 5.15%.

[0163] Experimental Example 3: Cytotoxicity Assay

[0164] The cytotoxicity of paclitaxel combined with antitumor drugs (chemotherapeutic agents, small molecule inhibitors, etc.) against pancreatic cancer cells such as BxPC-3, CFPAC-1, and PATU-8988T was investigated using the CCK8 assay. Cells (1000 cells / well) were seeded into 96-well plates and cultured overnight. Different concentrations of paclitaxel, different concentrations of antitumor drugs, and paclitaxel (1 μM) with different concentrations of antitumor drugs were added. After 72 hours, 10 μL of CCK8 working solution was added to each well. Cells were incubated in a cell culture incubator for 1-2 hours. The absorbance of each well (450 nm) was measured using a microplate reader, and the viability was calculated. Finally, the combination index (CI) of paclitaxel with various antitumor drugs was calculated using CompuSyn software.

[0165] Cytotoxicity of paclitaxel in combination with antitumor drugs, such as Figure 2 As shown in Figure a, paclitaxel exhibits a synergistic killing effect with various antitumor drugs against pancreatic cancer cells, as shown in the results. Figure 2 As shown in b, the synergistic indexes of different drugs vary.

[0166] Experimental Example 4: In vivo antitumor effects of albumin-paclitaxel twin drugs

[0167] KPC pancreatic cancer cell suspension was mixed with matrix gel at a 1:1 ratio and injected into the right axilla of C57BL / 6 mice, resulting in a tumor volume of 100 mm². 3 Around 10:00 AM, tumor-bearing mice were randomly divided into groups of 6 mice each; the treatments shown in Table 2 were performed respectively; tumor volume and mouse weight were recorded every two days; tumor volume change graph and survival curve were plotted; mouse weight change graph was plotted.

[0168] Table 2 Mouse Experiment Table

[0169]

[0170] Tumor volume changes in C57 mice bearing pancreatic cancer after intravenous administration, as shown in the figure Figure 3 As shown in Figure a, the changes in body weight in C57 mice bearing pancreatic cancer after intravenous administration are as follows: Figure 3 As shown in b.

[0171] The above embodiments are for illustrative purposes only and are not intended to limit the invention. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, all equivalent technical solutions also fall within the scope of this invention, and the patent protection scope of this invention should be defined by the claims.

[0172] The embodiments and / or implementation methods described above are merely preferred embodiments and / or implementation methods for implementing the technology of the present invention, and are not intended to limit the implementation methods of the technology of the present invention in any way. Any person skilled in the art can make some modifications or alterations to other equivalent embodiments without departing from the scope of the technical means disclosed in the content of the present invention, but they should still be regarded as the technology or embodiments that are substantially the same as the present invention.

[0173] This document uses specific examples to illustrate the principles and implementation methods of this application. The descriptions of the above embodiments are only for the purpose of helping to understand the methods and core ideas of this application. The above descriptions are only preferred embodiments of this application. It should be noted that due to the limitations of written expression, while there are objectively infinite specific structures, those skilled in the art can make several improvements, modifications, or changes without departing from the principles of this application, and can also combine the above technical features in an appropriate manner. These improvements, modifications, changes, or combinations, or the direct application of the inventive concept and technical solution to other situations without modification, should all be considered within the scope of protection of this application.

Claims

1. Use of paclitaxel conjugate nanoparticles for the preparation of a medicament for increasing the effect against PATU-8988T pancreatic cancer, characterized in that, The paclitaxel prodrug nanoparticle is composed of a paclitaxel prodrug compound and albumin, wherein the paclitaxel prodrug compound is bonded to the albumin; and the paclitaxel prodrug compound has the following structural formula: ， The R is a drug molecule, and the drug molecule is Navitoclax; and the Linker has the following structure: ； The paclitaxel prodrug compound is prepared by a coupling reaction of the drug molecule, the Linker and paclitaxel. In the preparation of the paclitaxel prodrug compound, the Linker molecule is reacted with NpCl in a solvent to form an intermediate SS-2, then SS-2 is reacted with PTX in dichloromethane to form PTX-SS-Np, and then PTX-SS-Np is reacted with the drug molecule in DMF to form the paclitaxel prodrug compound; the Linker molecule is SS-1, and has the following structure: ； The amount of SS-1 used is 20-30wt% of NpCl, the amount of PTX used is 40-80wt% of SS-2, and the amount of the drug molecule used is 20-140wt% of PTX-SS-Np.

2. A taxol conjugate compound, characterized in that, The paclitaxel prodrug compound has the following structural formula: , said R is a drug molecule, said drug molecule is Navitoclax; said Linker has the following structure: 。 3. A process for the preparation of the taxol conjugate compound of claim 2 comprising: The paclitaxel prodrug compound is prepared by a coupling reaction of the drug molecule, the Linker and paclitaxel. In the preparation of the paclitaxel prodrug compound, the Linker molecule is reacted with NpCl in a solvent to form an intermediate SS-2, then SS-2 is reacted with PTX in dichloromethane to form PTX-SS-Np, and then PTX-SS-Np is reacted with the drug molecule in DMF to form the paclitaxel prodrug compound; the Linker molecule is SS-1, and has the following structure: ； The amount of SS-1 used is 20-30wt% of NpCl, the amount of PTX used is 40-80wt% of SS-2, and the amount of the drug molecule used is 20-140wt% of PTX-SS-Np.

4. The method of claim 3, wherein the taxane compound is paclitaxel. In the coupling reaction, a solvent is used, and the solvent is one or more of dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, 1,4-dioxane, dimethyl sulfoxide, benzene, toluene, xylene, chlorobenzene, and o-dichlorobenzene; or, in the coupling reaction, a basic reagent is used, and the basic reagent is one or more of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal bicarbonates, triethylamine, tributylamine, trioctylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, piperidine, N-methylmorpholine, N-methylpiperidine, tetrahydropyrrole, triethylenediamine, and tetrabutylammonium hydroxide; or, in the coupling reaction, a condensing agent is used, and the condensing agent is one or more of EDCI, DCC and DIC.

5. A paclitaxel prodrug nanoparticle, comprising the paclitaxel prodrug compound of claim 2, and further comprising albumin, wherein the paclitaxel prodrug compound is bonded to the albumin. The albumin includes at least one of bovine serum albumin, human serum albumin, ovalbumin and recombinant human serum albumin; and the bonding is non-covalent bonding.

6. A method of preparing paclitaxel conjugate nanoparticles comprising: The paclitaxel conjugate compound of claim 2 is mixed with albumin in a complex solution to prepare paclitaxel conjugate nanoparticles.

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