A nucleic acid and chemical drug co-delivery polymer composition, preparation method and application thereof

Abstract

The present invention belongs to the field of biomedical materials, and discloses a polypeptide-modified nucleic acid and chemical drug co-delivery polymer composition, a preparation method and application thereof. Specifically disclosed is a polymer composition, comprising: (i) polyethyleneimine-polylactic acid-co-glycolic acid copolymer, which is represented by the following formula: PEI m ‑PLGA n , (ii) polyethylene glycol-polyaspartic acid covalently linked to the polypeptide, namely Di-PEG-PLD. The two materials are combined by electrostatic interaction to achieve the functional combination of targeting and co-loading of nucleic acid drugs and poorly soluble chemical drugs. The present invention also discloses a method for preparing a polymer composition and a method for co-loading nucleic acid drugs and poorly soluble anti-tumor drugs in a polymer composition.

Description

Technical Field

[0001] The present invention belongs to the field of biomedical materials, and specifically relates to a preparation method and application of a polypeptide-modified nucleic acid and chemical drug co-delivery carrier targeting prostate cancer, and specifically relates to a prostate cancer targeted delivery system composed of a polypeptide dimer connected with polyethylene glycol-polyaspartic acid and its application. Background Art

[0002] Prostate cancer is a malignant solid tumor with obvious heterogeneity. It has an insidious onset and no obvious specific symptoms in the early stage. It is one of the most common malignant tumors of the male urogenital system. Prostate cancer is hormone-dependent. Androgens bind to androgen receptors in prostate cancer cells to stimulate the growth of prostate cancer cells. Androgen deprivation therapy treats prostate cancer by blocking testicular androgens. However, as the disease progresses, the androgen receptor signaling pathway can still activate the pathway through direct and indirect reactivation mechanisms to promote disease progression.

[0003] In the early stage of tumor treatment, chemical drugs were mainly used, but their high toxicity to normal tissues limited their application. Small interfering RNA (siRNA), as a gene drug, is a new treatment model. siRNA induces RNA interference (RNAi) effect in vivo, specifically "silencing" pathogenic genes and playing a role in disease treatment. Chemical drugs and siRNA can play a synergistic role in tumor treatment and have a dual inhibitory effect on the proliferation of tumor cells.

[0004] Polyethyleneimine (PEI) is a cationic polymer rich in amino groups, which can effectively compress negatively charged genes and deliver them into cells. At the same time, the "proton sponge" property of PEI helps genes escape from lysosomes in cells and eventually enter the nucleus. The cytotoxicity of PEI is the main obstacle to its application. Many studies have shown that after PEI is modified, the cytotoxicity is greatly reduced and the transfection efficiency is less affected. Polylactic-co-glycolic acid (PLGA) is a biodegradable high molecular organic compound with good biocompatibility. It is a medical material approved by the US FDA. The cytotoxicity of PEI modified by PLGA is reduced, and PEI-PLGA can achieve the co-loading of genes and drugs. PLGA, as a hydrophobic core, can encapsulate lipophilic drugs, and PEI, as a hydrophilic shell, can bind to negatively charged genes. The use of polyethylene glycol-polyaspartic acid (PEG-PLD), on the one hand, polyethylene glycol (PEG) can achieve long circulation of nanoparticles in the body, and at the same time, polyaspartic acid (PLD) is pH sensitive, which is conducive to the passive targeting of nanoparticles to tumor sites.

[0005] The peptide (WQPDTAHHWATL) is a linear peptide that can selectively bind to the prostate-specific membrane antigen (PSMA) on the membrane of prostate cancer cells, which was screened by the phage library of Johns Hopkins University in the United States. Its dimer shows high affinity for PSMA. Using this peptide dimer as a target head can achieve active targeting of prostate cancer tissue. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide a new type of carrier material for co-delivery of nucleic acid drugs and chemical drugs targeting prostate cancer, namely a polypeptide-modified nucleic acid and chemical drug co-delivery polymer composition, and its preparation method and application.

[0007] In order to solve the technical problem of the present invention, the present invention provides the following technical solutions:

[0008] The first aspect of the technical solution of the present invention provides a polymer composition, comprising:

[0009] (i) Polyethyleneimine-polylactic acid-co-glycolic acid, which is represented by the following formula: PEI m -PLGA n ,

[0010] Wherein m and n represent the degree of polymerization of polyethyleneimine chain and polylactic acid glycolic acid chain respectively;

[0011] The degree of polymerization m of the polyethyleneimine chain is 2-200, preferably 5-22;

[0012] The molecular weight of the polyethyleneimine chain portion is 500-50000Da, preferably 1500-5000Da;

[0013] The degree of polymerization n of the polylactic acid glycolic acid chain is 12-300, preferably 15-60;

[0014] The molecular weight of the polylactic acid-glycolic acid chain portion is 800-30000Da, preferably 1000-30000Da;

[0015] In the present invention, the size of the polyethyleneimine chain portion and the polylactic acid glycolic acid chain portion can be expressed by either molecular weight or degree of polymerization, as long as there is no contradiction between them. When expressed by degree of polymerization, the lower right subscript is a unitless integer with m being 2-200 and n being 12-300, for example, PEI 15 -PLGA 20 When expressed in molecular weight, the lower right subscript is a number of 500-50000 or 3k-50k (for the polyethyleneimine chain portion) or a number of 800-30000 or 5k-30k (for the polylactic acid glycolic acid chain portion), such as PEI8000 -PLGA 10000 , for example PEI 8k -PLGA 10k .

[0016] (ii) Polyethylene glycol-polyaspartic acid covalently linked to the polypeptide, i.e. Di-PEG-PLD,

[0017] The sequence of the polypeptide is: CWQPDTAHHWATL-KLsy(biotin)-LTAWHHATDPQWC

[0018] The polyethylene glycol-polyaspartic acid covalently linked to the polypeptide, i.e., Di-PEG-PLD, has a molecular weight of 1000 to 10000 Da;

[0019] The degree of polymerization of polyaspartic acid is 8 to 50, preferably 10 to 30;

[0020] The molecular weight of polyaspartic acid is 1000 to 5000 Da, preferably 1200 to 3000 Da.

[0021] The second aspect of the technical solution of the present invention provides a method for preparing the polymer composition described in the first aspect, characterized in that:

[0022] (1) The preparation method of polyethyleneimine-polylactic acid-glycolic acid copolymer is:

[0023] 1) dissolving the carboxyl-terminated poly(lactic acid-co-glycolic acid) copolymer in an appropriate amount of dimethyl sulfoxide, adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide as catalysts, and activating at 20-40° C. for 2-4 hours;

[0024] 2) Add polyethyleneimine to the solution in 1), add a small amount of triethylamine, and continue the reaction at 20-40°C for 20-24 hours;

[0025] 3) After the reaction is completed, dialyze with a 500-3000Da dialysis bag for 48 hours and freeze-dry to obtain the copolymer PEI m -PLGA n ,;

[0026] (2) The preparation method of polyethylene glycol-polyaspartic acid covalently linked to a polypeptide is as follows:

[0027] The ratio of polyethylene glycol-polyaspartic acid to polypeptide substance is 2:1, and the reaction is carried out in a HEPEs solution of pH 8.0 under nitrogen protection for 16 to 24 hours. After the reaction is completed, the product is dialyzed with a 7000-10000Da dialysis bag for 24 hours and freeze-dried to obtain polyethylene glycol-polyaspartic acid covalently linked to the polypeptide, namely Di-PEG-PLD.

[0028] (3)Di-PEG-PLD / PEI m -PLGA n The preparation method is as follows: Di-PEG-PLD and PEI m -PLGA n Through electrostatic interaction, the C atom of the free carboxyl group of polyaspartic acid in Di-PEG-PLD binds to PEI m -PLGA n The amount of N atoms in PEI is 1:1, and the two solutions are mixed in equal volumes, allowed to stand for 30 minutes after mixing, and freeze-dried to obtain Di-PEG-PLD / PEI-PLGA.

[0029] In the above preparation method, further, the ratio of polylactic acid glycolic acid to dimethyl sulfoxide is 1g polylactic acid glycolic acid dissolved in 5-25ml dimethyl sulfoxide; the molar ratio of the added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide to polylactic acid glycolic acid is 1:20; and the volume ratio of triethylamine to dimethyl sulfoxide is 1:300.

[0030] The third aspect of the technical solution of the present invention provides an application of the polymer composition described in the first aspect, characterized in that: (i) it can be used to encapsulate nucleic acid drugs and poorly soluble anti-tumor drugs; and (ii) it can achieve targeting of prostate cancer cells.

[0031] Furthermore, the poorly soluble anti-tumor drugs encapsulated include paclitaxel, docetaxel, hydroxycamptothecin, and curcumin; and the encapsulated nucleic acid is selected from RNA or DNA.

[0032] The fourth aspect of the technical solution of the present invention is to provide a method for co-loading a nucleic acid drug and a poorly soluble anti-tumor drug in a polymer composition, characterized in that:

[0033] 1) dissolving polyethyleneimine-polylactic-co-glycolic acid copolymer and a poorly soluble anti-tumor drug in a certain amount of a mixed solvent of CH2Cl2 and CH3OH, adding the above solution dropwise into an appropriate amount of distilled water under magnetic stirring, and continuing stirring for 10 minutes to fully form colostrum, ultrasonically emulsifying the colostrum solution in an ice water bath for a certain period of time, and performing a reduced pressure rotary evaporation at 20°C for 30 minutes to remove the organic solvent, filtering the obtained nanosuspension with a 0.45 μm microporous filter membrane, and freeze-drying the obtained filtrate to obtain polyethyleneimine-polylactic-co-glycolic acid copolymer nanoparticles loaded with the poorly soluble anti-tumor drug;

[0034] 2) dissolving the nucleic acid drug in a certain amount of DEPC water, dissolving the nanoparticles obtained in 1) in a certain amount of distilled water, mixing the two in equal volumes, vortexing for 20-40 seconds, and incubating at room temperature for 30 minutes to obtain a polyethyleneimine-polylactic acid-co-glycolic acid nanoparticle solution carrying both the gene and the drug;

[0035] 3) The polyethyleneimine-poly(lactic-co-glycolic acid) copolymer nanoparticle solution and the Di-PEG-PLD solution were mixed in equal volumes and allowed to stand at room temperature for 30 minutes to obtain complete drug-loaded nanoparticles.

[0036] Furthermore, in step 1), the volume ratio of CH2Cl2 to CH3OH is 1:1; the power of ice-water bath ultrasonic emulsification is 150W, and the time is 10-20min; the mass ratio of polyethyleneimine-polylactic acid-co-glycolic acid copolymer to the poorly soluble anti-tumor drug is 50:1-5:1, and the preferred mass ratio is 45:1-10:1. In step 2), the size of the nucleic acid drug is 15-30bp.

[0037] Beneficial technical effects:

[0038] 1) PEI m -PLGA n The synthesis of both peptides and PEG-PLD adopts a one-step synthesis method, and the preparation method is simple; 2) block copolymers are used to simultaneously encapsulate anti-tumor drugs and gene drugs, without the need for other auxiliary materials such as co-solvents and solubilizers, and have small toxic side effects; 3) the peptide target head can achieve active targeting of prostate cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 : PEI prepared in Example 1 1800 -PLGA 2000 of 1 H-NMR spectrum

[0040] Figure 2 : PEI prepared in Example 1 1800 -PLGA 2000 Fourier transform infrared spectrum

[0041] Figure 3 : PLGA in Example 1 2000 Fourier transform infrared spectrum

[0042] Figure 4 : MALDI-TOF-MS spectrum of Di-PEG-PLD prepared in Example 1

[0043] Figure 5 : MALDI-TOF-MS spectrum of the polypeptide in Example 1

[0044] Figure 6 : Mal-PEG in Example 1 5k -PLD 10 MALDI-TOF-MS spectrum

[0045] Figure 7 : Di-PEG in Example 2 5k -PLD 10 and Mal-PEG 5k -PLD 10 1H-NMR spectrum comparison chart

[0046] Figure 8 : Di-PEG-PLD / DTX / siRNA / PEI in Example 2 1800 -PLGA 2000 Particle size potential diagram of composite nanoparticles

[0047] Fig. 9 : Di-PEG-PLD / DTX / siRNA / PEI in Example 2 1800 -PLGA 2000 TEM image of composite nanoparticles

[0048] Fig.10 :Carrier material Di-PEG-PLD / PEI 1800 -PLGA 2000 Cytotoxicity test results

[0049] Fig.11 :Gene silencing effect diagram of siRNA nanoparticles

[0050] Fig.12 :Di-PEG-PLD / DTX / siRNA / PEI 1800 -PLGA 2000 Composite nanoparticles inhibit cell proliferation in vitro DETAILED DESCRIPTION

[0051] Embodiment 1:

[0052] PEI 1800 -PLGA 2000 Synthesis

[0053] Weigh 100 mg PLGA 2000 -COOH was placed in a 50 mL round-bottom flask, 115.1 mg NHS (molar ratio 1:20), 191.5 mg EDC (molar ratio 1:20), and an appropriate amount of DMSO was added to dissolve, and stirred at room temperature for 2 h to activate PLGA 2000 After activation, 20 μL triethylamine and 90 mg PEI were added to the reaction system. 1800(molar ratio 1:1), and continue to react at room temperature for 20 hours. After the reaction is completed, dialyze in deionized water for 48 hours using a MWCO 2500 dialysis bag to obtain PEI 1800 -PLGA 2000 The final product was freeze-dried. The product obtained after freeze-drying was dissolved in deuterated DMSO and the nuclear magnetic resonance hydrogen spectrum ( 1 H-NMR), measured at 600M, the results are shown in Figure 1 .

[0054] Take the freeze-dried PEI 1800 -PLGA 2000 and PLGA 2000 Fourier transform infrared spectrum analysis was performed. The results are shown in Figure 2-3 PEI 1800 -PLGA 2000 1265.0cm appears in the infrared spectrum -1 、1542.2cm -1 、1635.9cm -1 The characteristic spectral bands of three amide bonds prove that the product was successfully synthesized.

[0055] Synthesis of Di-PEG-PLD

[0056] Weigh 20 mg of peptide and 69 mg of Mal-PEG 5k -PLD 10 (molar ratio 1:2) in a 50mL round-bottom flask, add 10mL of pH 8.0 Hepes buffer (0.1M), fill with nitrogen, and stir at room temperature for 20h. After the reaction, dialyze in deionized water for 24h using a MWCO 7000 dialysis bag, and the product is freeze-dried to obtain Di-PEG 5k -PLD 10 . Take the lyophilized Di-PEG 5k -PLD 10 The molecular weight was determined by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) of the reactants. Figure 4-6 .from Figure 4-6 It can be seen that the molecular weight of the polypeptide is about 3597.76, Mal-PEG 5k -PLD 10 The molecular weight of the two is about 5496.06, and the two react in a ratio of 1:2 to produce the target product Di-PEG 5k -PLD 10 The molecular weight is about 14591.75, which is close to the sum of the molecular weights of the two reactants, indicating that the target product is obtained.

[0057] Take the lyophilized Di-PEG 5k -PLD 10and Mal-PEG 5k -PLD 10 Dissolved in heavy water (D2O) to measure the nuclear magnetic resonance hydrogen spectrum (1H-NMR), the measurement frequency is 600M, the comparison of the two results is shown in the figure Figure 7 .Di-PEG 5k -PLD 10 The characteristic peak of the maleimide group at 6.5 ppm in the spectrum disappeared.

[0058] Example 2: Di-PEG-PLD / DTX / siRNA / PEI 1800 -PLGA 2000 Preparation and morphology observation of composite nanoparticles

[0059] Synthesize PEI according to Example 1 1800 -PLGA 2000 High molecular weight polymer, weigh 45 mg PEI 1800 -PLGA 2000 and 1mgDTX, dissolved in 2mLCH2Cl2 and 2mL CH3OH mixed solvent, added drop by drop into 16mL water with a dropper, stirring while adding. Stir for 10min after adding, ultrasonicate the reaction solution in an ice water bath for 10min at an ultrasonic power of 150W. Remove the organic solvent by rotary evaporation at room temperature, and filter the resulting solution through a 0.45μm filter membrane to obtain PEI. 1800 -PLGA 2000 / DTX nanoparticle solution. AR siRNA was dissolved in DEPC water and diluted to 5 pmol / μL. PEI 1800 -PLGA 2000 After mixing equal volumes of / DTX solution and siRNA, vortex for 30 seconds and incubate for 45 minutes, PEI was obtained. 1800 -PLGA 2000 / DTX / siRNA nanoparticles. According to the free -COOH in Di-PEG-PLD and PEI 1800 -PLGA 2000 The C / N ratio of the N atoms contained in the mixture was 1:1. The Di-PEG-PLD solution and PEI-PLGA / DTX / siRNA were mixed in equal volumes and allowed to stand at room temperature for 45 minutes to obtain Di-PEG-PLD / DTX / siRNA / PEI 1800 -PLGA 2000 Composite nanoparticles. The particle size and potential of the composite nanoparticles were measured using a laser particle size analyzer. The results are shown in Figure 8 The particle size of the composite nanoparticles is 101.4 nm and the potential is -20.1 mV.

[0060] The above nanoparticles were added to the plastic film, and a copper mesh was placed on the nanoparticle droplets. After 2 minutes, the copper mesh was removed and the liquid on the copper mesh surface was dried with filter paper. A drop of 1% phosphotungstic acid solution was added to the plastic film, and then the copper mesh was placed on the surface of the phosphotungstic acid droplets. After standing for 2 minutes, the copper mesh was removed and dried for 5 minutes. The morphology and size of the composite nanoparticles were observed under a transmission electron microscope (TEM). The results are shown in Figure 2. Fig. 9 .

[0061] Pharmacological experiments

[0062] In vitro cell experiments:

[0063] Experimental Example 1: Carrier Material Di-PEG-PLD / PEI 1800 -PLGA 2000 Cytotoxicity assay

[0064] The cytotoxicity evaluation experiment was determined by CCK-8 method. Lncap and PC3 prostate cancer cells in the logarithmic growth phase were taken and 8×10 3 / hole or 5×10 3 / well were inoculated into 96-well plates, with a volume of 200 μL per well, and cultured at 37°C and 5% CO2 for 24 h. After 24 h, Di-PEG-PLD / PEI 1800 -PLGA 2000 200 μL of RPMI-1640 culture medium with concentrations of 100, 10, 1, 0.1, and 0.01 μg / mL was added and incubated for 24 hours. After the incubation, the culture medium was aspirated and 100 μL of serum-free culture medium containing 10% CCK-8 was added to each well and incubated for 3 hours. The wells without drug treatment were used as control wells, and 6 replicate wells were set up for each well. The OD value at 450 mm was measured with an enzyme-labeled instrument. The cell survival rate (%) was calculated according to the following formula. The results are shown in Fig.10 . Different concentrations of Di-PEG-PLD / PEI 1800 -PLGA 2000 The cell viabilities were all above 90%, indicating that the carrier materials had low toxicity and good safety.

[0065]

[0066] Experimental Example 2: Gene silencing effect of siRNA-loaded nanoparticles

[0067] Human prostate cancer cells Lncap in the logarithmic growth phase were cultured at 20×10 4 The cells were plated at a density of 100 μg / well in a 6-well plate and cultured at 37°C and 5% CO2 for 24 h. After 24 h, the same dose of siRNA and blank carrier material (Di-PEG-PLD / PEI 1800 -PLGA 2000), and Di-PEG-PLD / NC.siRNA / PEI prepared according to the preparation method of the aforementioned Example 3 1800 -PLGA 2000 、Di-PEG-PLD / siRNA / PEI 1800 -PLGA 2000 Nanoparticles were added to the corresponding wells and cultured for 72 h. The protein expression level of the gene was measured. Fig.11 Compared with other groups, Di-PEG-PLD / siRNA / PEI 1800 -PLGA 2000 The protein expression level was significantly reduced, proving that Di-PEG-PLD / PEI 1800 -PLGA 2000 Effectiveness of delivering gene drugs.

[0068] Experimental Example 3: Di-PEG-PLD / DTX / siRNA AR / PEI 1800 -PLGA 2000 Anti-tumor cell proliferation effect of nanoparticles in vitro

[0069] Human prostate cancer cells Lncap in the logarithmic growth phase were cultured at 1×10 4 / well in a 96-well plate and cultured at 37°C, 5% CO2 for 24 hours. After 24 hours, the same dose of blank carrier material (Di-PEG-PLD / PEI 1800 -PLGA 2000 ), and Di-PEG-PLD / NC.siRNA / PEI prepared according to the preparation method of the aforementioned Example 3 1800 -PLGA 2000 、Di-PEG-PLD / siRNA / PEI 1800 -PLGA 2000 , Di-PEG-PLD / DTX / NC.siRNA / PEI 1800 -PLGA 2000 、Di-PEG-PLD / DTX / siRNA / PEI 1800 -PLGA 2000 Nanoparticles were added to the corresponding wells and cultured for 48 hours. Six replicate wells were set up in each group. After 48 hours, the culture medium was aspirated and 100 μL of serum-free culture medium containing 10% CCK-8 was added to each well and incubated for 3 hours. The wells without drug addition were used as control wells. The OD value at 450 mm was measured with an ELISA instrument to calculate the cell survival rate (%). The results are shown in Fig.12 Compared with other groups, Di-PEG-PLD / siRNA / PEI 1800 -PLGA 2000, Di-PEG-PLD / DTX / NC.siRNA / PEI 1800 -PLGA 2000 、Di-PEG-PLD / DTX / siRNA / PEI 1800 -PLGA 2000 The cell survival rate of the Di-PEG-PLD / DTX / siRNA / PEI 1800 -PLGA 2000 It has a good inhibitory effect on Lncap cell proliferation.

Claims

1. A polymer composition comprising: (i) Polyethyleneimine-polylactic acid-co-glycolic acid, which is represented by the following formula: PEI m -PLGA n , Wherein m and n represent the degree of polymerization of polyethyleneimine chain and polylactic acid glycolic acid chain respectively; The degree of polymerization m of the polyethyleneimine chain is 5-22; The molecular weight of the polyethyleneimine chain portion is 1500-5000Da; The degree of polymerization n of the polylactic acid glycolic acid chain is 15-60; The molecular weight of the polylactic-co-glycolic acid chain portion is 1000-30000Da; (ii) Polyethylene glycol-polyaspartic acid covalently linked to the polypeptide, i.e. Di-PEG-PLD, The sequence of the polypeptide is: CWQPDTAHHWATL-KLsy(biotin)-LTAWHHATDPQWC The polyethylene glycol-polyaspartic acid covalently linked to the polypeptide, i.e., Di-PEG-PLD, has a molecular weight of 1000 to 10000 Da; The degree of polymerization of polyaspartic acid is 10 to 30; The molecular weight of polyaspartic acid is 1200-3000 Da.

2. A method for preparing the polymer composition according to claim 1, characterized in that: (1) The preparation method of polyethyleneimine-polylactic acid-glycolic acid copolymer is: 1) dissolving the carboxyl-terminated poly(lactic acid-co-glycolic acid) copolymer in an appropriate amount of dimethyl sulfoxide, adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide as catalysts, and activating at 20-40° C. for 2-4 hours; 2) Add polyethyleneimine to the solution in 1), add a small amount of triethylamine, and continue the reaction at 20-40°C for 20-24 hours; 3) After the reaction is completed, dialyze with a 500-3000Da dialysis bag for 48 hours and freeze-dry to obtain the copolymer PEI m -PLGA n ; (2) The preparation method of polyethylene glycol-polyaspartic acid covalently linked to a polypeptide is as follows: The ratio of polyethylene glycol-polyaspartic acid to polypeptide substance is 2:1, and the reaction is carried out in a HEPEs solution of pH 8.0 under nitrogen protection for 16 to 24 hours. After the reaction is completed, the product is dialyzed with a 7000-10000Da dialysis bag for 24 hours and freeze-dried to obtain polyethylene glycol-polyaspartic acid covalently linked to the polypeptide, namely Di-PEG-PLD. (3)Di-PEG-PLD / PEI m -PLGA n The preparation method is as follows: Di-PEG-PLD and PEI m -PLGA n Bonded by electrostatic interaction.

3. The preparation method according to claim 2, characterized in that The ratio of polylactic acid glycolic acid to dimethyl sulfoxide is 1g polylactic acid glycolic acid dissolved in 5-25ml dimethyl sulfoxide; the molar ratio of the added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide to polylactic acid glycolic acid is 1:20; and the volume ratio of triethylamine to dimethyl sulfoxide is 1:

300.

4. The use of the polymer composition according to claim 1, characterized in that: (i) Used to encapsulate nucleic acid drugs and poorly soluble anti-tumor drugs; (ii) Prepare targeted prostate cancer cells.

5. The use according to claim 4, characterized in that: The poorly soluble anti-tumor drugs encapsulated include paclitaxel, docetaxel, hydroxycamptothecin and curcumin; the encapsulated nucleic acid is selected from RNA or DNA.

6. The method for co-loading a nucleic acid drug and a poorly soluble anti-tumor drug using a polymer composition according to claim 1, characterized in that: 1) dissolving polyethyleneimine-polylactic-co-glycolic acid copolymer and a poorly soluble anti-tumor drug in a certain amount of a mixed solvent of CH2Cl2 and CH3OH, adding the above solution dropwise into an appropriate amount of distilled water under magnetic stirring, and continuing stirring for 10 minutes to fully form colostrum, ultrasonically emulsifying the colostrum solution in an ice water bath for a certain period of time, and performing a reduced pressure rotary evaporation at 20°C for 30 minutes to remove the organic solvent, filtering the obtained nanosuspension with a 0.45 μm microporous filter membrane, and freeze-drying the obtained filtrate to obtain polyethyleneimine-polylactic-co-glycolic acid copolymer nanoparticles loaded with the poorly soluble anti-tumor drug; 2) dissolving the nucleic acid drug in a certain amount of DEPC water, dissolving the nanoparticles obtained in 1) in a certain amount of distilled water, mixing the two in equal volumes, vortexing for 20-40 seconds, and incubating at room temperature for 30 minutes to obtain a polyethyleneimine-polylactic acid-co-glycolic acid nanoparticle solution carrying both the gene and the drug; 3) The polyethyleneimine-poly(lactic-co-glycolic acid) copolymer nanoparticle solution and the Di-PEG-PLD solution were mixed in equal volumes and allowed to stand at room temperature for 30 minutes to obtain complete drug-loaded nanoparticles.

7. The method for co-loading a nucleic acid drug and a poorly soluble anti-tumor drug according to claim 6, characterized in that: In step 1), the volume ratio of CH2Cl2 to CH3OH is 1:1; the power of ice-water bath ultrasonic emulsification is 150 W, and the time is 10-20 min.

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