Multifunctional Nanoplatforms Loaded With Photosensitizer Of Indocyanine Green(ICG) And Chemotherapeutic Drug Of Doxorubicin(DOX) For Combination Therapy Of Cancer

Nowadays cancer has become the leading threat to human health owing to the increasing rate of incidence and mortality.Many existing therapeutic methods,such as surgery,chemotherapy,radiotherapy,gene therapy,and immunotherapy,display unique advantages and limitations toward the treatment of various types of cancers.The complexity,diversity and heterogeneity of tumors considerably challenge the accurate selection of desirable therapeutics,despite enormous input in manpower,materials and financial resources.One of the current focuses in clinical anticancer investigations is to convert monotherapy to combination therapy,which aims to achieve improved therapeutic efficacy under mutual complementarities among individual modality.Moreover,many versatile medical imaging techniques have enabled the early diagnosis of cancer and accurate location of tumors.Nowadays,there is an urgent demand to develop novel theranostic platforms,which can realize combination therapy under the synergism of multitherapeutics,and allow precise tumor detection under cooperative imaging guidance.In recent years,phototherapy activated by light irradiation has drawn increasing attention towing to its noninvasive property during applications.Particularly,photodynamic therapy and photothermal therapy have shown promising capability with minimal side effects and high selectivity.Moreover,multiple stimuli-responsive drug-loaded nanoparticles are developed to realize spatiotemporal control of drug release with higher tumor-targeting performance and ameliorate adverse effects to normal tissues.Therefore,a rapid and economical synthetic strategy is highly desirable to develop drug-loaded nanoparticles as novel imaging contrast agents and multifunctional therapeutic drugs for cancer treatment,which are responsive to various exogenous or endogenous stimuli.In this thesis,we firstly proposed a multifunctional hollow mesoporous Prussian blue?HMPB?based nanoplatform for triple-modal combination therapy.Specifically,HMPB NPs were loaded with ICG and DOX?denoted as HMPB@PEI/ICG/DOX or HPID NPs?to realize a combination treatment of photothermal/photodynamic/chemotherapy activated by NIR laser irradiation.After intravenous injection,HPID NPs rapidly accumulated in tumor regions through the enhanced permeability and retention effect and were internalized intracellularly through endocytosis.The highly responsive photo-induced hyperthermia enabled rapid and controllable drug release.The fluorescent of ICG also allowed for real-time monitoring nanodrug biodistribution in vivo evaluating the therapeutic outcome.This HPID NP-mediated combination therapy demonstrated a remarkable antitumor effect both in vitro and in vivo compared with any of individual therapeutic modality.Then,we proposed a multifunctional SF@MnO₂ nanoparticle-based platform.SF?silk fibroin?as a reductant and a template was used to synthesize SF@MnO₂ nanoparticles via a biomineralization-inspired crystallization process in an extremely facile way.Because of their mesoporous structure as well as abundant amino and carboxyl terminal residues,SF@MnO₂nanoparticles were co-loaded with photodynamic agent ICG and chemotherapeutic drug DOX to form a SF@MnO₂/ICG/DOX?SMID?nanocomplex.The obtained product was highly reactive with high level endogenous hydrogen peroxide?H₂O₂?in tumor microenvironment,which was decomposed into O₂ to enhance tumor-specific photodynamic therapy?PDT?.Moreover,SMID nanocomplex produced a strong and stable photothermal effect upon near-infrared laser irradiation for photothermal therapy?PTT?owing to the distinct photothermal response of SF@MnO₂ and stably conjugated ICG.The concurrent NIR fluorescence and magnetic resonance imaging in vivo both indicated effective tumor-specific enrichment of SMID nanoparticles via enhanced permeability and retention effect.The results further verified that SMID nanoparticles remarkably improved tumor inhibitive efficacy through combination PTT/PDT/chemotherapy with minimal systemic toxicity and adverse side effect.