CN115105605B - Preparation and application of active targeting anti-tumor self-assembled nanoparticle - Google Patents

Preparation and application of active targeting anti-tumor self-assembled nanoparticle Download PDF

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CN115105605B
CN115105605B CN202110288266.0A CN202110288266A CN115105605B CN 115105605 B CN115105605 B CN 115105605B CN 202110288266 A CN202110288266 A CN 202110288266A CN 115105605 B CN115105605 B CN 115105605B
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tumor
cisplatin
palbociclib
nanoparticle
self
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CN115105605A (en
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黄园
向宇成
李炼
陈李强
刘晨冬
周洲
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Sichuan University
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Sichuan University
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Abstract

The invention discloses preparation and application of an active targeting anti-tumor self-assembled nanoparticle. The nanoparticle contains a combination of a metal platinum complex and a CDK4/6 kinase inhibitor, palbociclib, as active ingredients and a tumor targeting ligand modifier. The metal platinum complex is at least one of cisplatin, carboplatin, oxaliplatin, nedaplatin, cisplatin and heptaplatin for clinical medication. The conjugate is a covalent conjugate formed by a metal platinum complex and palbociclib. The nanoparticle obtained by the invention can release free drugs by utilizing the platinum-oxygen bond reduction responsive fracture in the structure. To further increase the stability and targeting of the nanoparticle, a tumor targeting ligand modifier is added, which is a covalent conjugate of a tumor active targeting ligand and an amphiphilic block copolymer. The invention further improves the curative effect of the anti-tumor chemotherapeutic by utilizing the active targeting effect of the conjugate of the metal platinum complex and the palbociclib and the tumor targeting ligand modifier.

Description

Preparation and application of active targeting anti-tumor self-assembled nanoparticle
Technical Field
The invention relates to preparation and application of self-assembled nanoparticles for actively targeting anti-tumor, in particular to self-assembled nanoparticles formed by a drug conjugate of a metal platinum complex and a CDK4/6 kinase inhibitor palbociclib and a tumor targeting ligand modifier and application thereof, and belongs to the technical field of medicines.
Background
Cancer is a serious threat to human life and health. It is estimated by the World Health Organization (WHO) that cancer will become the leading cause of death and the most important factor affecting life expectancy growth in humans in the 21 st century. Although cancer treatments are now becoming increasingly diverse, chemotherapy is still one of the most important approaches. However, the clinical requirement cannot be met only by single drug treatment, and the two-drug combination strategy cannot achieve the ideal effect due to the different properties of different drugs such as pharmacokinetics. In addition, chemotherapeutic agents often exhibit adverse effects on other tissues and organs after off-target, limiting their clinical use. For this reason, the search for combined chemotherapeutic drug formulations with tumor targeting is a great need for cancer treatment.
Compared with free medicines, the nanometer medicine delivery system can remarkably improve the pharmacokinetic properties of the medicines, prolong the blood circulation time of the medicines, and can utilize the high permeability and retention effect of tumor tissues to passively target to tumor sites. However, relying solely on passive targeting is insufficient because 1) there is no specific reaction between the cells and the nanoparticles, resulting in less uptake of the drug; 2) Nanoparticles do not have high permeability and retention effects in all tumor tissues. Compared with normal cells, the surface of tumor cells often overexpresses certain specific antigens or receptors, and after the surface of the nanoparticle is modified by the corresponding ligand, the nanoparticle loaded with the chemotherapeutic drug enters tumor tissues and can be rapidly accumulated in the tumor and enter the cells to play a role through the specific recognition effect between the ligand and the receptor. Therefore, the ligand with tumor active targeting ability is further modified on the surface of the nanoparticle, so that the nanoparticle can endow the nanoparticle with the tumor active targeting ability, and the accumulation and the drug effect of the drug in a target tissue are further increased.
At present, most of nano-particles have low drug loading, complex preparation process and difficult mass production. The method has the advantages that the hydrophilic and hydrophobic self-assembly of the drug is utilized to form nanoparticles, the drug is endowed with the function of a carrier, the strategy can avoid the defect of complex preparation process of the traditional nanoparticles, and simultaneously the dosage of auxiliary materials is greatly reduced, but the defects that the content fluctuation of different batches of drugs in the preparation process is large, the proportion of the combined drugs cannot be accurately controlled and the like exist. Two or more drugs are connected through chemical reaction to form a conjugate, and then the conjugate is spontaneously assembled in water to form nanoparticles, so that the content of the drugs and the proportion of the combined drugs can be well controlled, and the composition has good clinical application potential. Therefore, it is extremely important to design a drug self-assembled nano-drug delivery system with active targeting capability.
The metal platinum complex realizes the anti-tumor effect by complexing with DNA molecules and inhibiting the DNA replication of tumor cells, and is a clinically used broad-spectrum anti-tumor drug. Among them, cisplatin is a representative of metal platinum complex, but because of serious toxic and side effects and easy drug resistance, new medication strategies are needed to optimize the clinical effects. Palbociclib is the first approved specific cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitor worldwide that selectively inhibits CDK4/6 kinase activation to block tumor cell cycle, prevent cell division proliferation, but is not effective in inducing apoptosis, so once treatment is stopped, tumors resume growth leading to recurrence. The combination of cytotoxic metal platinum complexes with palbociclib may achieve synergistic antitumor effects. However, simple co-administration of a metal platinum complex with palbociclib only shows poor clinical effects due to differences in pharmacokinetic properties and the like of the two drugs, and also cannot achieve stimulus-responsive drug release and the like by simple combination. How to make the metal platinum complex and palbociclib form a conjugate, and self-assemble in water to form nanoparticles, so that a nano drug delivery system for realizing tumor targeting by using tumor targeting ligand modification has not been reported yet.
Disclosure of Invention
In order to solve the problems of poor effect and poor targeting of the combined chemotherapeutic drugs to be used clinically at present, the inventor carries out creative research on covalent connection of a metal platinum complex and a CDK4/6 inhibitor palbociclib to form a drug conjugate, and then self-assembles the drug conjugate in water to form nanoparticles, and on the basis, a proper amount of ligand modifier is added to play a role in stabilizing agent and endowing the nanoparticles with targeting so as to increase accumulation of drugs at tumor positions, improve toxicity to tumor cells, inhibit tumor metastasis and further improve the curative effect of the anti-tumor chemotherapeutic drugs.
One of the purposes of the invention is to overcome the defects and shortcomings of simple combination of chemotherapeutic drugs, optimize the pharmacodynamics and pharmacokinetic properties of the combined application of the chemotherapeutic drugs, increase the targeting property of the chemotherapeutic drugs, reduce untoward effects caused by off-target, and provide an active targeting anti-tumor self-assembled nanoparticle.
The invention also aims to provide the application of the self-assembled nanoparticle of the metal platinum complex and the palbociclib drug conjugate and the active targeting ligand modifier with tumor active targeting in anti-tumor combined chemotherapy drugs. The drug conjugate can increase the susceptibility of tumor cells to the metal platinum complex by increasing ROS in tumor tissue using the CDK4/6 inhibitor, palbociclib, in combination with the metal platinum complex. In addition, the active targeting nanoparticle can increase accumulation of the chemotherapeutic drug in tumor tissues and remarkably improve the anti-tumor treatment effect of the chemotherapeutic drug.
The aim of the invention is achieved by the following technical scheme: an active targeting anti-tumor self-assembled nanoparticle comprises a metal platinum complex as an active ingredient, a drug conjugate of a CDK4/6 kinase inhibitor palbociclib and a nanoparticle formed by self-assembling a tumor active targeting ligand modifier in water.
The active targeting anti-tumor self-assembled nanoparticle can also contain one or at least two pharmaceutically acceptable carriers.
The active targeting anti-tumor self-assembled nanoparticle can be further prepared into various forms such as injection and the like, and various dosage forms of medicaments can be prepared according to a conventional method in the pharmaceutical field.
The metal platinum complex is at least one of cisplatin, carboplatin, oxaliplatin, nedaplatin, cisplatin and heptaplatin for clinical medication; cisplatin is preferred.
The drug conjugate of the metal platinum complex and the palbociclib is formed by covalent coupling of at least one of cisplatin, carboplatin, oxaliplatin, nedaplatin, leptoplatin and heptylplatin with the palbociclib; preferably cisplatin-palbociclib drug conjugate.
The cisplatin-palbociclib drug conjugate is preferably prepared by the following method:
1) Dispersing cisplatin in deionized water, heating, adding hydrogen peroxide solution, mixing and stirring for 1h. The mixture was concentrated under vacuum to give yellow crystals. Centrifugally collecting crystals, namely cis-platinum hydroxylation derivative c, c, t- [ Pt (NH) 3 ) 2 Cl 2 (OH) 2 ]。
2) Dissolving cisplatin hydroxylation derivative and succinyl anhydride in dimethyl sulfoxide, mixing and stirring for 24h. Dripping the mixed solution into diethyl ether to obtain yellow precipitate, washing the precipitate with dichloromethane, and vacuum drying to obtain cis-platinum carboxylated derivative c, c, t- [ Pt (NH) 3 ) 2 Cl 2 (O 2 CCH 2 CH 2 COOH) 2 ]。
3) The palbociclib and cisplatin carboxylated derivative are dispersed in dimethyl sulfoxide, and then dimethyl sulfoxide solution dissolved with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine is added, mixed and stirred for 24 hours. Purifying the yellow transparent mixed liquid by column chromatography to obtain yellow powder, namely the cisplatin-palbociclib conjugate.
The active targeting ligand is integrin alpha v β 3 Receptor targeting peptides (integrin alpha) v β 3 receptor targeting peptide, iRGD), transferrin (Tf), EGF receptor targeting peptide (epidermal growth factorreceptortargetingantibody, cetuximab), VEGF receptor targeting peptide (vascular endothelial growth factor targeting peptide, K237), death receptor 5monoclonal antibody (deathxepost 5monoclonal antibody,AMG655), ligand polypeptide of low density lipoprotein (Low Density Lipoproteinligand, angiopep-2), HER-2 targeting antibody (human epidermal receptor-2 targeting antibody,Trastuzumab), laminin receptor targeting peptide (Lamininreceptor targeting peptide, YIGSR), flavin mononucleotide (flavin mononucleotide), lactose (lactose), mannitol (mannitol), hepsphoryl (Hepatic phospholipid), transparencyAt least one of hyaluronic acid (folic acid) and folic acid (folic acid); preferably iRGD.
The amphiphilic block copolymer is at least one of distearoyl phosphatidylethanolamine-polyethylene glycol copolymer (DSPE-PEG), polycaprolactone-polyethylene glycol copolymer (PCL-PEG), polylactic acid-polyethylene glycol copolymer (PLA-PEG) and polystyrene-polyethylene glycol copolymer (PS-PEG); preferably DSPE-PEG.
The tumor active targeting ligand iRGD modifier is covalent conjugate DSPE-PEG-iRGD of iRGD peptide and distearoyl phosphatidylethanolamine-polyethylene glycol copolymer DSPE-PEG, and the mass of the covalent conjugate DSPE-PEG-iRGD accounts for 1% -20% of the total mass of the nanoparticle; preferably 10%.
The tumor active targeting ligand iRGD modifier DSPE-PEG-iRGD is preferably prepared by the following method:
DSPE-PEG, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide are dissolved in DMSO, heated, mixed and stirred for 30min to activate carboxyl groups on DSPE-PEG-COOH. Then adding iRGD-NH 2 Mixing and stirring were continued for 24h. Transferring the reaction mixture into a dialysis bag with the molecular weight cut-off of 1000Da, dialyzing in distilled water for 48 hours, and freeze-drying to obtain DSPE-PEG-iRGD.
The self-assembled nanoparticle with active targeting is preferably prepared by the following method:
cisplatin-palbociclib conjugate was mixed with DSPE-PEG-igd in DMSO and then rapidly poured into distilled water with stirring to give a clear yellow solution. Transferring the mixed solution into a ultrafiltration tube with the molecular weight cutoff of 10kDa, and centrifuging to remove DMSO, thereby obtaining the iRGD-PCN nanoparticle.
The tumors comprise breast cancer, ovarian cancer, prostate cancer, testicular cancer, lung cancer, nasopharyngeal cancer, esophagus cancer, lymphoma, head and neck squamous carcinoma, thyroid cancer, osteosarcoma and multiple myeloma; preferably triple negative breast cancer.
The application of the self-assembly of the drug conjugate of the metal platinum complex and the CDK4/6 kinase inhibitor palbociclib and the amphiphilic active targeting ligand iRGD modifier to the preparation of the anti-tumor active targeting preparation is provided.
The application of the drug combination of the metal platinum complex and the CDK4/6 kinase inhibitor palbociclib and the tumor active targeting ligand iRGD modifier to the preparation of the anti-tumor active targeting preparation is that the drug combination of the metal platinum complex of the anti-tumor chemotherapeutic drug and the CDK4/6 kinase inhibitor palbociclib and the tumor active targeting ligand iRGD modifier are used as active ingredients.
The nanoparticle formed by self-assembling the metal platinum complex and the drug conjugate of the CDK4/6 kinase inhibitor palbociclib and the tumor active targeting ligand iRGD modifier can effectively induce apoptosis of tumor cells, thereby inhibiting the progress of triple negative breast cancer.
The nano particles formed by self-assembling the metal platinum complex and the drug conjugate of the CDK4/6 kinase inhibitor palbociclib and the tumor active targeting ligand iRGD modifier can obviously increase the cytotoxicity to tumor cells, inhibit the in-vivo metastasis of tumors and increase the accumulation of drugs at tumor positions, thereby realizing the active targeting combined chemotherapy drug treatment.
Compared with the prior art, the invention has the following advantages and effects:
1. the invention provides a novel combined chemotherapeutic drug strategy, which relates to the use of a metal platinum complex and a CDK4/6 inhibitor palbociclib. The metal platinum complex has serious toxic and side effects and is easy to generate drug resistance, and a new medication strategy is needed to optimize the clinical effect. The palbociclib can block the tumor cell cycle and prevent the tumor cell from dividing and proliferating, and the combination of the metal platinum complex and the palbociclib can realize the synergistic anti-tumor effect. However, simple concurrent use of only a metal platinum complex with palbociclib may show poor clinical effects due to differences in pharmacokinetic properties and the like. The metal platinum complex and the palbociclib are covalently coupled to prepare a drug conjugate, and the amphiphilic property of the drug conjugate is utilized to self-assemble in water to form nanoparticles, so that certain targeting capability is further provided for the nanoparticles, and the combination effect of the chemotherapeutic drugs can be enhanced.
2. Chemotherapeutic agents often show serious toxic side effects after off-target due to their cytotoxic effects, whereas passive targeting agents have been controversial in recent years due to their poor clinical response. The invention provides a preparation and application method of active targeting anti-tumor self-assembled nanoparticles, which increases the accumulation of drug-loaded nanoparticles in tumor tissues by modifying tumor active targeting ligands on the surfaces of the nanoparticles, and is expected to further optimize the clinical application of metal platinum complexes and palbociclib while reducing adverse reactions. Therefore, the technology has great social significance.
3. The self-assembled nanoparticle can release free drugs by utilizing the platinum-oxygen bond reduction responsive fracture in the structure, has high drug loading capacity and simple prescription process, and is expected to realize further industrial production and clinical transformation. Therefore, the technology has great economic value.
Description of the drawings:
embodiments of the present invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 shows a schematic representation of the synthesis of cisplatin carboxy derivatives and DSPE-PEG-iRGD.
FIG. 2 shows cisplatin hydroxylated derivatives c, c, t- [ Pt (NH) 3 ) 2 Cl 2 (OH) 2 ]A kind of electronic device 1 HNMR spectra.
FIG. 3 shows cisplatin carboxylated derivatives c, c, t- [ Pt (NH) 3 ) 2 Cl 2 (OH)(O 2 CCH 2 CH 2 COOH) 2 ]A kind of electronic device 1 HNMR spectra.
FIG. 4 shows cisplatin-palbociclib conjugate 1 HNMR and ESI-MS spectra.
FIG. 5 shows DSPE-PEG-iRGD 1 HNMR and MALDI-TOF-MS spectra.
FIG. 6 shows a schematic of nanoparticle preparation and a transmission electron microscope picture.
FIG. 7 shows particle size, potential characterization of self-assembled nanoparticles.
Figure 8 shows a graph of drug release time profile for the reductive response of self-assembled nanoparticles.
FIG. 9 is a graph showing the uptake of coumarin 6-loaded self-assembled nanoparticles by confocal microscopy cells.
FIG. 10 is a graph showing the quantitative measurement of uptake of coumarin 6-loaded self-assembled nanoparticles by cells using an enzyme-labeled instrument.
FIG. 11 shows a graph of the effect of self-assembled nanoparticles on the cell viability of MDA-MB-231 cells.
FIG. 12 shows the effect of self-assembled nanoparticles on tumor growth in tumor-bearing mice.
FIG. 13 shows a graph of tumor inhibition of self-assembled nanoparticles against tumor-bearing mice.
FIG. 14 shows the effect of self-assembled nanoparticles on the body weight of tumor-bearing mice.
The specific embodiment is as follows:
the present invention will be described in further detail with reference to examples, but embodiments of the present invention are not limited thereto. The invention is further illustrated in detail below with reference to examples, but it will be understood by those skilled in the art that the invention is not limited to these examples and the preparation methods used. Moreover, those skilled in the art will appreciate that the invention may be practiced with equivalent, combined, improvements, or modifications, which are within the scope of the invention.
EXAMPLE 1 Synthesis of cisplatin-palbociclib conjugate
200mg of cisplatin was dispersed in 5.6mL of deionized water, heated to 50℃and 9.6mL of 30% hydrogen peroxide solution was added thereto, and the mixture was stirred for 1 hour. The mixture was concentrated under vacuum to give yellow crystals. Centrifugally collecting crystals, namely cis-platinum hydroxylation derivative c, c, t- [ Pt (NH) 3 ) 2 Cl 2 (OH) 2 ]. By using 1 HNMR characterizes its structure and the results are shown in fig. 1 and fig. 2.
50mg of cisplatin hydroxylated derivative and 30mg of succinic anhydride were dissolved in 4ml of dimethyl sulfoxide, and the mixture was stirred for 24 hours. Dripping the mixed solution into diethyl ether to obtain yellow precipitate, washing the precipitate with dichloromethane for 3 times, and vacuum drying to obtain cis-platinum carboxylated derivative c, c, t- [ Pt (NH) 3 ) 2 Cl 2 (O 2 CCH 2 CH 2 COOH) 2 ]. By using 1 HNMR characterizes its structure and the results are shown in fig. 3.
40mg of ParbosCilnidin and 24mg of cisplatin carboxylated derivative were dispersed in 2ml of dimethyl sulfoxide, then 500. Mu.l of dimethyl sulfoxide solution in which 17mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 5.4mg of 4-dimethylaminopyridine were dissolved was added, and the mixture was stirred for 24 hours. Purifying the yellow transparent mixed liquid by column chromatography (200-300 mesh silica gel, dichloromethane: methanol=10:1) to obtain yellow powder, namely cisplatin-palbociclib conjugate. By using 1 HNMR and ESI-MS characterization, results are shown in fig. 4.
FIG. 4 1 HNMR spectra showed-NH with cisplatin-palbociclib conjugate at 6.4ppm 3 Characteristic hydrogen peak, and-C-NH-C-characteristic hydrogen peak of palbociclib (10.1 ppm) and-NH thereof 3 The peak area ratio of the characteristic hydrogen peak (6.4 ppm) was 2:6, demonstrating successful synthesis of cisplatin-palbociclib conjugate. Further ESI-MS mass spectrometry showed that the detected molecular weight (mw= 1393.3) was consistent with the calculated molecular weight of the cisplatin-palbociclib conjugate, indicating successful conjugate synthesis.
Example 2 Synthesis of DSPE-PEG-iRGD
19.6mg of carboxyl-derivatized distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-PEG-COOH), 2.1mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.8mg of N-hydroxysuccinimide were dissolved in DMSO, heated to 50℃and mixed with stirring for 30min to activate the carboxyl groups on DSPE-PEG-COOH. Then 8.0mgiRGD-NH is added 2 Mixing and stirring were continued for 24h. Transferring the reaction mixture into a dialysis bag with the molecular weight cut-off of 1000Da, dialyzing in distilled water for 48 hours, and freeze-drying to obtain DSPE-PEG-iRGD. Adopts nuclear magnetic resonance hydrogen spectrum 1 HNMR) and matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) are presented in fig. 5.
FIG. 5 1 HNMR spectra show that the characteristic peak belonging to iRGD can be observed in DSPE-PEG-iRGD, wherein the characteristic peak belongs to iRGD, and the characteristic peak is 7-7.5 ppm. Further MALDI-TOF-MS spectra showed that the detected molecular weight (mw= 3728.41) was consistent with the calculated molecular weight of DSPE-PEG-igbd, demonstrating successful synthesis of DSPE-PEG-igbd.
Example 3 preparation and characterization of self-assembled nanoparticle iRGD-PCN
mu.L of DMSO (10 mg/ml) containing cisplatin-palbociclib conjugate was mixed with 2.6. Mu.L of DMSO solution containing DSPE-PEG-iRGD (10 mg/ml) and then rapidly injected into 2ml of pure water under stirring to give a clear yellow solution. Transferring the mixed solution into a ultrafiltration tube with the molecular weight cutoff of 10kDa, and centrifuging to remove DMSO, thereby obtaining the iRGD-PCN nanoparticle. The unmodified nanoparticle PEG-PCN is prepared by the same method, and DSPE-PEG-iRGD is replaced by methoxy-terminated distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-PEG-OMe). The particle size was further measured by a dynamic light scattering method, and the structure was observed by a scanning electron microscope, and the results are shown in fig. 6 and 7.
Further examining the release of the reduction response, coumarin 6 was loaded into the nanoparticles (2. Mu.l of DMSO solution containing 10mg/ml coumarin 6 was added to the above mixed solution, and pure water was added dropwise), and after concentrating the nanoparticles by ultrafiltration, the nanoparticles were transferred into dialysis bags (molecular weight cut-off 8-14 kDa). Each dialysis bag was placed in 50ml of different buffers 1) phosphate buffer, pH7.4, 0mM glutathione; 2) phosphate buffer, pH7.4, 10mM glutathione; 3) phosphate buffer, pH6.8, 0mM glutathione; 4) phosphate buffer, pH6.8, 10mM glutathione; 5) phosphate buffer, pH5.0, 0mM glutathione; 6) phosphate buffer, pH5.0, 10mM glutathione. At the prescribed time point, 100. Mu.l of the solution was removed and 100. Mu.l of the corresponding blank buffer was added. The fluorescence intensity of the solutions at each time point was measured by a microplate reader (Varioskan LUX, thermo Fisher Scientific), and the results are shown in fig. 8.
The transmission electron microscope image results of FIG. 6 show that both PEG-PCN and iRGD-PCN exhibit a more regular circular appearance. The results in FIG. 7 show that the hydrated particle size of PEG-PCN is about 40nm, the polydispersity is 0.15, the particle size of iRGD-PCN is 54nm, and the polydispersity is 0.17. The prepared drug conjugate is loaded into the nano-particles, so that the drug loading rate of cisplatin can reach 14.5%, the drug loading rate of palbociclib can reach 45.66%, and the drug loading rate is obviously higher than that of other nano-drug delivery systems. In the invention, cisplatin molecules are oxidized, hydroxyl is introduced, and carboxyl derivatization is performed, and the tetravalent platinum compound has the characteristic of reducing drug release, so that as shown in the result of figure 8, in a phosphate buffer solution without glutathione, the iRGD-PCN nanoparticle only releases about 40% of coumarin 6 after 48h incubation. In the solution containing glutathione, the release of coumarin 6 is greatly increased, and the cumulative release can reach 80% under the condition of pH5.0, which shows that the iRGD-PCN nano-particles can be disintegrated under the reducing condition to further release the medicine.
Example 4 confocal microscopy of cellular uptake of self-assembled nanoparticles
Triple negative breast cancer MDA-MB-231 cells were plated at 2X 10 5 cells/well were inoculated into 12-well plates and placed in a cell culture incubator for 24h. The tests were carried out separately for PEG-PCN carrying coumarin 6 and iRGD-PCN carrying coumarin 6:
1) Coumarin 6-loaded PEG-PCN: 2ml of RPMI1640 medium containing PEG-PCN (containing 10% FBS) was added with 6 equivalents of coumarin at 5. Mu.g/ml;
2) iRGD-PCN carrying coumarin 6: 2ml of RPMI1640 medium containing iRGD-PCN (containing 10% FBS) was added with 6 equivalents of coumarin at 5. Mu.g/ml;
after incubation for 0.5h,2h,6h, each was washed 2 times with phosphate buffer. Nuclei were labeled with 4, 6-diamidino-2-phenylindole (DAPI), washed 2 times with phosphate buffer (pH 7.4) and blocked with 80% glycerol-water mixture, and observed with confocal microscopy (Carl Zeiss LSM 800, germany). The results are shown in FIG. 9.
As shown in FIG. 9, green fluorescence of coumarin 6 was detected in tumor cells by confocal microscopy, where both the fluorescence intensity in tumor cells increased with time after incubation of PEG-PCN and iRGD-PCN, while the intracellular fluorescence after treatment with iRGD-PCN was significantly higher than that after treatment with PEG-PCN nanoparticles, indicating that modification with iRGD was able to increase cellular uptake of nanoparticles.
Example 5 quantitative detection of cellular uptake of iRGD-PCN nanoparticles by an enzyme-labeled Instrument
Triple negative breast cancer MDA-MB-231 cells were plated at 1X 10 4 cells/well were inoculated in 96-well plates and placed in a cell incubator for 24h. Cell numbers were first corrected using the resazurin method. The supernatant from the 96-well plate was discarded and 200. Mu.l of RPMI1640 medium (containing 10. Mu.g/ml resazurin was added to each well10% FBS) was incubated at 37℃for 1 hour, and the fluorescence intensity was measured by an enzyme-labeled instrument (Varioskan LUX, thermo Fisher Scientific) (excitation wavelength: 530nm, emission wavelength: 590 nm). The supernatant containing resazurin was discarded, and the supernatant was washed three times with phosphate buffer, and the samples were divided into PEG-PCN carrying coumarin 6 and iRGD-PCN carrying coumarin 6 for the test:
1) Coumarin 6-loaded PEG-PCN: 2ml of RPMI1640 medium containing PEG-PCN (containing 10% FBS) was added with 6 equivalents of coumarin at 5. Mu.g/ml;
2) iRGD-PCN carrying coumarin 6: 2ml of RPMI1640 medium containing iRGD-PCN (containing 10% FBS) was added with 6 equivalents of coumarin at 5. Mu.g/ml;
after incubation for 0.5h,2h,6h, each was washed 2 times with phosphate buffer. The cells and intracellular nanoparticles were destroyed by adding a mixed solvent (water: dimethyl sulfoxide=1:1), and the fluorescence intensity (excitation wavelength: 466nm, emission wavelength: 504 nm) was measured by an enzyme-labeled instrument (Varioskan LUX, thermo Fisher Scientific). The results are shown in FIG. 10.
As shown in fig. 10, the intracellular fluorescence intensity of cells incubated with the iRGD-modified nanoparticles after 6h incubation was 2.66 times that of the unmodified nanoparticles. The results further demonstrate that modification with iRGD can increase cellular uptake of nanoparticles.
Example 6 investigation of cytotoxicity of iRGD-PCN nanoparticles on MDA-MB-231 cells
Triple negative breast cancer MDA-MB-231 cells were plated at 3X 10 3 cells/well were inoculated into 96-well plates and placed in a cell culture incubator for 24h. The experiments were performed in a control group, a cisplatin group, a palbociclib group, a cisplatin-in-palbociclib group, and a PEG nanoparticle-in-iRGD nanoparticle group:
1) Control group: mu.l of RPMI1640 medium (containing 10% FBS) was added to each well;
1) Cisplatin group: 200 μl of RPMI1640 medium (containing 10% FBS) up to 6.71 μg/ml cisplatin (equidiluted) was added per well;
2) Palbociclib group: 200 μl of RPMI1640 medium (containing 10% FBS) up to 20.0 μg/ml palbociclib (equi-dilution) was added per well;
3) Cisplatin in combination with palbociclib group: 200 μl of RPMI1640 medium (containing 10% FBS) containing up to 20.0 μg/ml palbociclib+6.71 μg/ml cisplatin (equidiluted) was added per well;
4) PEG-PCN group: 200 μl of RPMI1640 medium (containing 10% FBS) containing up to 20.0 μg/ml of Pabosini equivalent PEG-PCN (equidiluted) was added per well;
5) Group iRGD-PCN: 200 μl of RPMI1640 medium (containing 10% FBS) containing up to 20.0 μg/ml palbociclib equivalent of iRGD-PCN (equidiluted) was added per well;
after 48h incubation, the drug-containing medium was discarded, replaced with fresh medium and incubation continued for 24h. After 24h, 20. Mu.l of thiazole blue phosphate solution (MTT, 5 mg/ml) was added to each well, after 4h incubation, the supernatant was discarded, the phosphate buffer was washed 2 times, 150. Mu.l of dimethyl-dissolving formazan was added, and absorbance was measured at 570nm using a microplate reader (Varioskan LUX, thermo Fisher Scientific). The results are shown in FIG. 11.
Fig. 11 shows that each of the dosing groups showed concentration-dependent cytotoxicity, and that cisplatin combined with palbociclib showed significantly greater cytotoxicity than cisplatin or palbociclib alone, demonstrating that both cisplatin and palbociclib were able to synergistically kill tumors. The effect of cisplatin administration was evaluated by the CompuSyn software according to the method of Chou-Talay. The synergy index (CI, CI <0.9 represents synergy; CI >1.1 represents antagonism; CI <1.1 represents addition) of both under different degrees of growth inhibition (Fa, affected cell proportion) is calculated, and under half growth inhibition conditions, the synergy index is 0.3+/-0.02 less than 1, which indicates that the combination of the two is synergistic.
The cytotoxicity of the nanoparticle group is weaker than that of the free drug, probably because the drug release of the nanoparticle needs to be reduced by substances such as intracellular glutathione, and the free drug can be rapidly diffused into cells to play a role. It is notable that the cell viability of the cells after the iRGD-PCN treatment was significantly lower than that of the PEG-PCN group. At the highest concentration, PEG-PCN nanoparticles do not inhibit cell viability by more than 50%, while IC of modified iRGD-PCN nanoparticles 50 (Pabosini equivalent) was 14.25.+ -. 3.4. Mu.g/ml, which indicated that iRGD-PCN was more cytotoxic than PEG-PCN.
Example 7 influence of self-assembled nanoparticles on tumor growth in tumor-bearing mice
MDA-MB-231 cells were cultured in RPMI1640 medium (containing 10% FBS) in a cell culture box containing 5% (v/v) CO2 at 37℃and then digested with 0.25% pancreatin (containing 0.02% disodium ethylenediamine tetraacetate), washed once with phosphate buffer (pH 7.4), and counted. The cells were resuspended in sterile phosphate buffer (pH 7.4) to adjust the cell density to 3X 10 6 cells/ml. Each mouse (nude mice, BALB/c, female) was inoculated with 100. Mu.l of the cell suspension to the third pair of right breast pads, and an MDA-MB-231 orthotopic tumor mouse model was established. (7-8 weeks of week, purchased from Sichuan Chengdu Biotechnology Co., ltd.) the major diameter (a) and minor diameter (b) of the transplanted tumor were measured with a vernier caliper, and the tumor volume (V) was calculated as follows: v=a×b 2 /2. When the tumor grows to 100mm 3 At this time, animals were randomly divided into 6 groups of 5 animals each, and administration was started simultaneously.
The administration method comprises the following steps:
1) Control group: saline was injected intravenously through the tail of the mice on days 1,3, and 5, respectively;
2) Cisplatin group: normal saline (containing cisplatin equivalent 1.08 mg.kg) was intravenously injected via the tail of the mice on days 1,3, and 5, respectively -1 )；
3) Palbociclib group: on days 1,3,5, physiological saline (containing palbociclib equivalent 3.2mg kg) was injected intravenously through the tail of the mice, respectively -1 )；
4) Cisplatin in combination with palbociclib group: normal saline (containing cisplatin equivalent 1.08 mg.kg) was intravenously injected via the tail of the mice on days 1,3, and 5, respectively -1 And palbociclib equivalent 3.2 mg/kg -1 )；
5) PEG-PCN group: PEG-PCN-containing physiological saline (cisplatin equivalent 1.08 mg. Kg) was intravenously injected via the tail of the mice on days 1,3, and 5, respectively -1 And palbociclib equivalent 3.2 mg/kg -1 )；
6) Group iRGD-PCN: physiological saline containing iRGD-PCN (containing cisplatin equivalent 1.08 mg.kg) was intravenously injected via the tail of the mice on days 1,3,5, respectively -1 And palbociclib equivalent 3.2 mg/kg -1 ). Mice were sacrificed at the end of the experiment and in situ tumor volume growth curves and body weights were recordedThe results are shown in fig. 12, 13 and 14.
The results show that the tumors in the physiological saline group grow rapidly, and the cisplatin, the palbociclib and the cisplatin palbociclib can inhibit the tumor growth to a small extent when being combined (the tumor inhibition rates are 30.40+/-4.15%, 32.38 +/-5.67% and 38.18+/-1.83% respectively). This is because of the poor tumor accumulating capacity of free drugs in vivo. The tumor volume of PEG-PCN mice increases more slowly and the tumor inhibition rate is higher (51.00+/-1.46%). This is because the nanoparticles are self-assembled and then accumulated in the tumor site. Further, the iRGD-PCN has a stronger tumor-inhibiting ability (80.18±5.61%) than the PEG-PCN group because of further increase of intratumoral accumulation of the nanoparticles after modification of iRGD and uptake thereof by tumor cells. The mice weight did not decrease during the experiment, indicating that the iRGD-PCN has better biocompatibility and does not cause systemic toxicity to cause weight decrease.

Claims (5)

1. An actively targeted anti-tumor self-assembled nanoparticle is characterized in that: comprises an active ingredient and an amphipathic tumor targeting ligand modifier, wherein the components are self-assembled in water to form nanoparticles; the active ingredient is a drug conjugate formed by cisplatin and a CDK4/6 kinase inhibitor palbociclib, the amphiphilic tumor targeting ligand modifier is a covalent conjugate of an active targeting ligand and an amphiphilic block copolymer, and the self-assembled nanoparticle is applied to anti-breast cancer treatment;
the drug conjugate is prepared by the following method: 1) Dispersing cisplatin in deionized water, heating, adding hydrogen peroxide solution, mixing and stirring for 1h; concentrating the mixture under vacuum to give yellow crystals; centrifugally collecting crystals, namely cis-platinum hydroxylation derivatives c, c, t- [ Pt (NH 3) 2Cl2 (OH) 2]; 2) Dissolving cisplatin hydroxylation derivative and succinyl anhydride in dimethyl sulfoxide, mixing and stirring for 24 hours; dripping the mixed solution into diethyl ether to obtain yellow precipitate, washing the precipitate with dichloromethane, and vacuum drying to obtain cis-platinum carboxylated derivative c, c, t- [ Pt (NH 3) 2Cl2 (O2 CCH2CH2 COOH) 2]; 3) Dispersing palbociclib and cisplatin carboxylated derivatives in dimethyl sulfoxide, then adding dimethyl sulfoxide solution dissolved with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine, mixing and stirring for 24 hours; purifying the yellow transparent mixed liquid by column chromatography to obtain yellow powder, namely cisplatin-palbociclib conjugate;
the active targeting ligand is integrin alpha v β 3 Receptor targeting peptide iRGD;
the amphiphilic block copolymer is distearoyl phosphatidylethanolamine-polyethylene glycol copolymer DSPE-PEG.
2. The actively targeted anti-tumor self-assembled nanoparticle of claim 1, wherein: the drug conjugate is a covalent conjugate formed by cisplatin and palbociclib, and the molar ratio of the cisplatin to the palbociclib is 1:0.1-1:10.
3. The actively targeted anti-tumor self-assembled nanoparticle of claim 1, wherein: in the preparation of the nanoparticle, the mass of the amphiphilic tumor targeting ligand modifier accounts for 1-20% of the total mass of the nanoparticle.
4. The actively targeted anti-tumor self-assembled nanoparticle of claim 1, wherein: the active targeting anti-tumor self-assembled nanoparticle is further prepared into an injection form.
5. Use of the anti-tumor self-assembled nanoparticle of claim 1 in the preparation of an anti-breast cancer formulation.
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