Blood Cell Membrane-coated Gold Nanorods For Photothemal Therapy Of Tumors

Cancer treatment is one of the most difficult medical challenges nowadays.Although great advances in cancer research have led to improvement in patient survival over the past decades,current cancer therapy is still unsatisfactory due to tumor heterogeneity and complex tumor microenvironment.There is an urgent need for more specific drug with fewer side effects,more efficient drug delivery,and quicker onset.Nanoparticle drug delivery systems are recently widely used because of their excellent improvement of drug accumulation in tumors through passive and active targeting ways.Gold nanorods,with its high photo-thermal conversion efficiency,ease to modification,and less harm to normal tissue,work well in photothermal therapy of tumors.With the development of biomimetic nanotechnology,nanoparticles modified with natural biological components to avoid clearance by the immune system and replicate the biological interactions have shown great potential in biomedical application.In this study,blood cell membrane-coated gold nanorods were combined with tumor microenvironment modulation and tumor vessel damage strategy to improve photothermal therapy of gold nanorods against different kinds of tumors.In Chapter One,a new photothermal therapy strategy of pancreatic ductal adenocarcinoma（PDA）was developed by combination of tumor microenvironment modulation and advanced design of red blood cell（RBC）membrane-coated gold nanorods（MGNR）.It was shown that MGNR exhibited high colloidal stability,strong photothermal therapeutic efficacy,and longer circulation with a t_1/2 of 14.9 h.Tumor microenvironment modulation by cyclopamine treatment successfully disrupted the extracellular matrix of PDA and improved tumor blood perfusion with an improvement rate of 74.9%.The accumulation of MGNR significantly increased in tumors and therefore produced higher photothermal efficiency in vivo.Finally,with the integrated advantages of tumor microenvironment regulation and long-circulation biomimetic MGNR,effective photothermal therapy of PDA was achieved with a tumor growth inhibition rate of 81.1%.In Chapter Two and Chapter Three,fibrin-targeting peptide CREKA-conjugated RBC membrane-coated gold nanorods（CMGNR）and platelet membrane-coated gold nanorods（PGNR）were prepared for self-amplified phtothermal therapy of breast cancer.Both CMGNR and PGNR showed high stability and strong targeting capacity.The binding test showed that CMGNR bound with blood clot or fibrin more strongly than MGNR.As the breast cancer was rich in blood vessels,blood vessels could be damaged by photothermal effect of CMGNR and PGNR,inducing large amount of expression of fibrin and thrombus,causing more CMGNR binding and accumulation in tumors.After photothermal treatment by CMGNRs,the tumor temperature reached 58.2oC,leading to significant tumor growth inhibition.Because of the adhesion between platelet membrane and injured vessels,PGNR bound well to blood clot and collagen.24 h after injection and photothermal damage of blood vessles,the accumulation of PGNR in tumors increased by 55.8%compared with MGNR.Furthermore,PGNR inhibited the tumor growth by 73.3%through photothermal therapy.In Chapter Four,RBC-platelet hybrid membrane-coated gold nanorods（PMGNR）were developed for photothermal therapy of multiple myeloma using a self-amplified targeting strategy.PMGNR showed high stability and characteristic properties of both source cells–the adhesion ability with collagen and blood clot like platelets and the long circulation time like red blood cell.It was shown the accumulation of PMGNR in tumors was increased by 1.64-fold compared with MGNRs.Furthermore,the tumor temperature reached 62.6oC after photothermal therapy,and the photothermal therapy significantly inhibited tumor growth.In summary,in this study four types of blood cell bionic nanoparticles were designed.Different treatment strategies were adopted according to the different tumor microenvironment characteristics of three types of tumors,to effectively improve the photothermal therapeutic effect against tumors.