Cell Membrane Biomimetic Nano Drug Delivery System In Gastrointestinal Cancer Therapy

Gastrointestinal(GI)tumor is a major disease threatening human health.The incidence of colorectal and gastric cancers in China ranks 2nd and 3rd among all tumors,after lung cancer;both gastric and colorectal cancers have an inflammatory-cancer transformation course,and most patients suffer from long-term chronic gastritis or enteritis before cancer is diagnosed.Long-term administration of tumors using conventional chemotherapeutic agents leads to the development of systemic adverse effects.This has led to many limitations in the treatment of conventional drugs against GI tumors.Therefore,the development of novel targeted drug delivery systems to mitigate systemic adverse effects is an urgent challenge in the treatment of GI tumors.In recent years,bionanodelivery systems,especially cell membrane-encapsulated nanoparticles,have shown better therapeutic efficacy against inflammation and tumors due to their good biocompatibility and specific targeting ability.Such bionanomaterials typically contain two key components: the nanoparticle core and the cell membrane outer layer.Such a hybrid design not only allows the biomimetic nanoparticles to inherit the complex biological functions of cell membranes,but also to function as nanoparticles to improve drug properties.Tumor cells tend to exhibit stronger self-adhesion between cells due to the presence of their surface interactions,so the tumor cell membrane wrapped nanoparticles will penetrate the tumor tissue more easily.Tumor cell membrane-coated nanoparticles are more readily taken up by homologous tumor cells compared to erythrocyte membranes.Therefore,it becomes possible to target tumor tissues using tumor cell membrane-derived nanoparticles,which can actively target and infiltrate into solid tumors and even track and capture circulating tumor cells in the blood.Therefore,the construction of novel homologous tumor cell membrane-encapsulated biomimetic nanoparticles is a new and effective way to treat GI tumors.Objective: In our previous study,we found that Eph A2 and METTL3 are highly expressed in gastrointestinal tumors and are potential targets for targeted therapy.METTL3 is closely related to m6 A modification,and high expression of METTL3 leads to an abnormal increase in intracellular m6 A modification and promotes tumor cell proliferation.We hope to construct novel cell membrane biomimetic nanoparticles drug delivery systems around these two targets.To make the synthesized nanoparticles with stronger tumor targeting in vivo and ex vivo,we introduced the technique of bio-orthogonal click chemistry to improve the efficiency of nanoparticle targeting to tumors.To achieve active targeting ability of nanoparticles,we plan to bind YSA peptide(targeting Eph A2)to the cell membrane on the surface of biomimetic nanoparticles by click chemistry.We hypothesize that the synthesized cell membrane biomimetic nanoparticles will have better tumor targeting properties than conventional biomimetic nanoparticles.This study aims to find new drug targets for GI tract tumors and to develop novel and effective targeted drug delivery systems for gastrointestinal tumors.Methods:(1)Validate the relationship between Eph A2 inhibitor ALW and colorectal tumor resistance.(2)Validate the inhibitory effect of METTL3 inhibitor STM on gastric cancer cells or tissues.(3)Validate the binding ability of YSA peptide to gastrointestinal tumor cells and detect the targeting effect of YSA-modified nanoparticles on tumor cells.(4)Validate whether click chemistry occurs in vivo.(5)Synthesize PLGA-ALWDBCO@CCM-YSA and PLGA-STM-DBCO@CCM-YSA nanoparticles to verify the targeting effect of nanoparticles with colorectal cancer or gastric cancer,respectively.(6)To detect the targeting effect of the synthesized drug-loaded biomimetic nanoparticles on colorectal cancer resistant cells or gastric cancer.(7)To detect the effect of PLGA-STMTAT@CCM-YSA on tumor cell metastasis inhibition.(8)Combine the synthesized biomimetic nanoparticles with immune checkpoint inhibitors to obtain better tumor treatment.(9)Test the biosafety of nanomaterials.Results:(1)The Eph A2 inhibitor ALW was able to overcome oxaliplatin resistance in colorectal cancer.(2)The METTL3 inhibitor STM2457 was able to inhibit proliferation and promote apoptosis in a variety of gastric cancer cell lines.(3)Modification of YSA peptides improved tumor targeting of the biomimetic nanoparticles in rheumatoid mice.(4)Both extracellularly and intracellularly DBCO was able to interact with the cell membrane surface of.(5)our synthesized PLGA-ALW-TAT@CCM-YSA and PLGA-STM-TAT@CCM-YSA homologous tumor cell membrane biomimetic nanoparticles could better target and treat transplanted tumors in mice.(6)PLGA-STM-TAT@CCM-YSA could inhibit the metastasis of mouse melanoma cells.(7)STM was able to reduce PD-L1 expression in gastric cancer cells,and PLGA-STM-TAT@CCM-YSA in combination with anti-PD1 could enhance tumor immunotherapy.(8)The biosafety of nanomaterials was good.Conclusions: 1.Cancer cell membrane bionanoparticles carrying rece ptor tyrosine kinase Eph A2 inhibitors or m6 A modification inhibitors can treat gastrointestinal tract tumors,overcome oxaliplatin resistance in colorectal cancer or inhibit tumor metastasis.2.Cancer cell me mbrane biomimetic nanoparticles in combination with immune chec kpoint inhibitors can enhance antitumor immunotherapeutic effects.