The Design And Appilcations Of Biologic Membrane Biomimetic Nano-drug Delivery System For Cancer Therapy

Objective:Recently,nano-drug delivery systems have attracted widespread attention in the field of pharmaceutical preparations.However,high immunogenicity and potential safety risks of materials hinder the clinical translation of nanomedicine.The biomaterials with higher safety have become a trend for the clinical translation of nanomedicine.Based on this,three strategies for biomimetic modification of cell membranes via different preparation processes were designed and proposed:1.The strategy of synergistic chemotherapy based on the red blood cell membrane biomimetic modified self-assembled nano-drug(p-QDF@M);2.The strategy of chemo-immunotherapy based on the cancer cell membrane biomimetic modified nanogel(NG_P@M_I);3.The strategy of enhanced chemotherapy strategy based on cell self-processing extracellular vesicle derived nano-drug delivery systems(c-NP_D@M).Methods:1.Synergistic chemotherapy strategy based on p-QDF@M.1)Preparation of p-QDF@M by extrusion method.2)Investigate the cellular uptake behavior of p-QDF@M.3)Investigate the antitumor effect of p-QDF@M in vitro and clarify the mechanism.4)Study the biodistribution and pharmacokinetics of p-QDF@M.5)Investigate the anti-tumor effect of p-QDF@M in vivo.2.Chemotherapy combined with immunotherapy strategy based on NG_P@M_I.1)Preparation of NG_P@M_I by extrusion method.2)Study the in vivo biodistribution and pharmacokinetics of NG_P@M_I.3)Investigate the homologous targeting effect of NG_P@M_I.4)Evaluate the ability of NG_P@M_I to induce immunogenic death.5)Investigate the anti-tumor effect of NG_P@M_I and the mechanism of combined immunotherapy.3.Enhanced chemotherapy strategy based on c-NP_D@MV.1)Preparation of c-NP_D@MVs through cellular"endocytosis-efflux"behavior.2)Characterized the structure and protein composition of c-NP_D@MV.3)Study the effect of autophagy level on c-NP_D@MV production.4)Investigate the intracellular transport of c-NP_D.5)Investigate the ability of c-NP_D@MV to penetrate deep into the tumor and its anti-tumor effect in vitro.6)Investigate the anti-tumor effect of c-NP_D@MV in vivo.Results:1.p-QDF@M could efficiently encapsulate DOX and quercetin,and induce apoptosis and autophagic cell death in tumor cells by up-regulating the level of intracellular reactive oxygen species.In an orthotopic breast cancer model,p-QDF@M could significantly inhibit tumor growth and lung metastasis.2.NG_P@M_I could co-encapsulate PTX and IL-2,and achieve tumor-targeted delivery and acid-stimulated controlled drug release.Strong tumor inhibitory effect and long-term anti-tumor effect in an orthotopic breast cancer model were demonstrated.NG_P@M_I could promote DC maturation,T cell infiltration and activation in tumor tissue,and induce the formation of anti-tumor immune memory.3.c-NP_D transported in tumor cells via multivesicular body and autophagic multivesicular body pathways,and realized the biomimetic modification of EVs biofilm in the process.Up-regulation of autophagy in tumor cells could increase the production of c-NP_D@MV,which could enhance the efficiency of DOX in killing tumor cells and exhibit a strong anti-tumor effect in an orthotopic breast cancer mouse model,with a tumor inhibition rate of 79.87%.Conclusion:This paper revolves around"improving drug delivery efficiency and anti-tumor effect".A variety of cell membrane biomimetic nanomedicines were successfully developed and exhibited enhanced antitumor effects.Provide new ideas for the development of nanomedicine.Innovations:(1)The formation of core framework in p-QDF@M didn’t depend on other pharmaceutical excipients or materials,which was beneficial to the clinical transformation of nano-drugs.(2)NG@M could possess acid-responsive controlled drug release and tumor-selective homologous targeting efficiency,and could further achieve effective synergy between chemotherapy and immunotherapy.(3)A new method for biomimetic modification of nanomedicines through cellular self-processing has been developed.