Preparation And Antitumor Activity Of Drug-loaded Polydopamine Nanoparticles Camouflaged By Stem Cell Membrane

Background:Malignant tumor is one of the most important diseases that endanger human health.How to give effective treatment to curb the development of malignant tumors is the focus and difficulty faced by the current medical field,especially oncology workers.At present,there are many methods for the treatment of malignant tumors,such as surgery,chemotherapy,radiotherapy,biotherapy and so on,in which chemotherapy plays an indispensable role.clinically,most cancer patients need chemotherapy in the course of their treatment.With the development of antineoplastic drugs,chemotherapeutic drugs with different mechanisms have emerged,such as anthracyclines,taxanes,platinum,topoisomerase inhibitors and so on.However,after clinical application of chemotherapeutic drugs,patients often have a variety of adverse reactions,ranging from nausea,vomiting and hair loss to myelosuppression,liver and kidney injury and even life-threatening.The reason is that after the chemotherapeutic drugs enter the blood circulation through intravenous or oral administration,on the one hand,they reach the tumor site to kill tumor cells,on the other hand,the drugs will stay in other parts of the body and produce toxicity to normal tissues and cells.Therefore,if we use the existing technology to increase the targeting of chemotherapeutic drugs,so that the drugs are specifically accumulate in the tumor site and the concentration in normal tissues can reduce,it can not only effectively alleviate the adverse reactions of patients,but also improve the antitumor effect of drugs.Nano-drug delivery system usually refers to the drug delivery system whose particle size is less than 1000 nm.In particular,nanoparticles smaller than 200 nm can not only delay the clearance time in vivo and increase the concentration in tumor tissue,but also have unique advantages such as larger specific surface area,better drug loading performance,easy modification and so on,thus they have become the focus of biomedical research.Polydopamine nanoparticles,as a melanin-like polymer,are produced by oxidative polymerization of dopamine under certain condition.Because of simple synthesis,easy modification and good biocompatibility,they are widely used in the field of biomedicine.The surface of polydopamine is rich in aromatic rings,amino groups,hydroxyl groups and other functional groups.Doxorubicin and other drugs can be loaded on the surface by ?-? conjugation and hydrogen bond interaction.Under acidic conditions(tumor microenvironment),this interaction is destroyed,resulting in the release of doxorubicin from the surface of polydopamine into the tumor tissue to achieve the purpose of controlled drug release.However,when unmodified nanoparticles enter the body,they will activate the reticuloendothelial system and be recognized and cleared by macrophages,thus reducing the circulation time in vivo and limiting the application of nano-drug delivery system.The surface modification of nanoparticles by chemical or physical methods can improve this problem,in which using natural cell membrane to camouflage nanoparticles is one of the most promising methods.Mesenchymal stem cells,which have low immunogenicity and tumor tendency,are the research focus in the field of medicine.If mesenchymal stem cell membrane is used to modify doxorubicin-loaded polydopamine nanoparticles,these camouflaged nanomaterials will be able to obtain the characteristics of stem cell membrane.For one thing,they can avoid phagocytosis of reticular endothelial cells and prolong the action time of drugs;for another they can target the tumor site to improve antitumor effect of drugs and reduce adverse reactions.Objective:To analyze the characteristics of adverse reactions of cancer patients during the first chemotherapy in our department.To construct polydopamine nanoparticles camouflaged by mesenchymal stem cell membrane and loaded with doxorubicin,and to study the drug release ability of biomimetic nanomaterials and their inhibitory effect on the growth of human esophageal cancer cell line Eca-109,so as to provide a theoretical basis for clinically improving the antitumor effect of chemotherapeutic drugs and possibly improving adverse reactions.Methods:Patients who received chemotherapy for the first time in our department were collected,and the main adverse reactions were recorded and statistically analyzed.Polydopamine nanoparticles were prepared by aqueous oxidation method,and the particle size was determined by transmission electron microscope.Doxorubicin was loaded on the surface of polydopamine at appropriate temperature and pH conditions.Human umbilical vein-derived mesenchymal stem cells were cultured and collected.The cells were destroyed by hypotonic lysis and repeated freezing and thawing,then the stem cell membrane fragments were obtained by differential centrifugation.After extruded repeatedly by polycarbonate porous filter membrane,the stem cell membrane was wrapped on the surface of nanoparticles by water bath ultrasound to synthesize biomimetic nano-drug.The biomimetic nano-drug was placed in neutral and acidic environment respectively,and the release of doxorubicin in different time periods was determined by spectrophotometer.Different concentrations of biomimetic nano-drug were used to treat human esophageal cancer cell line Eca-109.The effect of biomimetic nano-drug on the proliferation of cancer cells was detected by CCK-8 method.Results:1.The main adverse reactions of cancer patients during the first chemotherapy in our department were nausea,vomiting,fatigue,alopecia,diarrhea,constipation and abnormal sensation.The most common adverse reactions were nausea and vomiting,with an incidence of 65%,followed by fatigue,with an incidence of 57%.2.Polydopamine nanoparticles with a particle size of 78±9nm were synthesized and the chemotherapeutic drug doxorubicin was loaded on the surface of polydopamine with a drug loading rate of 18%.3.The structure of cell membrane on the surface of biomimetic nano-drug was observed by transmission electron microscope.4.The release of doxorubicin from biomimetic nano-drug was pH-responsive.The amount of doxorubicin released at pH 5.5 was about 11% after 48 hours,while only about 5% at pH 7.4.5.At the same concentration of doxorubicin,the killing effect of biomimetic nanodrug on esophageal cancer cell line Eca-109 was higher than nanoparticles without stem cell membrane,and the difference was statistically significant.Conclusion:1.Traditional chemotherapeutic drugs have great side effects and high incidence of adverse reactions,which increase the physical and mental burden of patients.It is of great significance to explore new anti-tumor drugs.2.Doxorubicin-loaded polydopamine nanoparticles camouflaged by stem cell membrane were synthesized successfully.3.The new biomimetic nano-drug has the ability of pH-responsive drug release,and the camouflage using stem cell membrane can enhance the anti-tumor effect of nano-drug.