Engineering Macrophage-derived Exosomes For Targeted Chemotherapy Of Triple-negative Breast Cancer

Triple-negative breast cancer(TNBC)is the most metastatic and recurrent subtype of breast cancer.Owing to the lack of therapeutic targets the clinical treatment of TNBC limited options.Chemotherapy and surgical intervention are the only treatments for TNBC.However,the effectiveness of chemotherapeutics is restrained by the shortcomings of chemotherapeutic drugs,such as fast clearance,poor targeting,easy resistance,and high toxicity.The development of nanotechnology has provided the possibility to reduce the in vivo clearance rate of chemotherapeutics and improve the targeting rate.However,synthetic nanoparticles still retain a certain degree of toxicity to the human body.As an endogenous extracellular vesicle,exosomes naturally have the advantages of low immunogenicity,non-toxicity and long blood circulation time.This has given exosomes great potential as a drug delivery vehicle.In addition,exosomes derived from different types of cells still have certain functions of cells.For example,immune cell-derived exosomes can mimic the immune cell to target tumor cells.Based on the above research background,this study constructed a biomimetic drug delivery system.Specifically,cellular-mesenchymal to epithelial transition factor(c-Met)binding peptide-modified macrophage-derived exosomes are used to coat doxorubicin nanoparticles(MEP-D)for non-toxic,efficient,targeted delivery doxorubicin to triple-negative breast cancer site,which allow doxorubicin to better perform its anti-tumor effect while reducing its side effects.This study is divided into three chapters.The first chapter mainly addresses the preparation process and characterization of this biomimetic drug delivery system,including the loading of doxorubicin into nanoparticles(PL-D),and exosomal membrane coated doxorubicin nanoparticles(EP-D)and modifying exosomal membrane with c-Met binding peptide(MEP-D).Then,this biomimetic drug deliver system was characterized by particle size,Zeta potential,transmission electron microscope imaging,identification of identifying proteins,encapsulation efficiency and drug loading content.The second chapter describes the anti-triple-negative breast cancer proliferation effect of MEP-D at the cellular level.The triple-negative breast cancer cell line MDA-MB-231 was used as the research object,and studies on cytotoxicity,cell uptake,and cell efficacy of this delivery platform were carried out The third chapter is based on the in vitro research of Chapter 2,by establishing nude mice models bearing in situ triple-negative breast cancer tumors,including its biological safety,targeting efficiency,anti-tumor proliferation efficiency.The characterization data of MEP-D showed the successful construction of MEP-D,and the size and structure are stable.In vitro cell experiments,MEP-D greatly improved the uptake efficiency of DOX by MDA-MB-231 cells,leading to more apoptosis.The results of in vivo studies on tumor-bearing mice confirm that MEP-D effectively prolongs the circulation time of DOX.MEP-D has a significant targeting effect on tumor sites and effectively inhibits tumor growth.All these results proved that MEP-D is a promising drug delivery strategy for the chemotherapy of triple-negative breast cancer.Figure[20]table[6]reference[47]...