Stimuli-Responsive Nanomaterials For Tumor Theranostics

According to the global cancer statistics in 2020,the number of newly diagnosed cancer cases and deaths is increasing,and cancer has become one of the main diseases threatening human health and survival.At present,the commonly used diagnostic methods mainly include:computer tomography(CT)imaging,magnetic resonance imaging(MRI)and ultrasound(US)imaging.These diagnostic strategies are difficult to accurately recognize the tumor tissue in its early stage,leading to most of the patients in the middle and late stage missed the best opportunity for therapy.What’s more,traditional cancer treatments including chemotherapy,radiotherapy and surgical treatment are faced with many shortcomings,such as poor specificity,strong toxicity,high therapeutic resistance,and easy recurrence.Therefore,it is urgent to understand the characteristics of the tumor microenvironment(TME)and explore new alternative theranostics to improve the efficiency of tumor diagnosis and therapies,reduce side effects and decrease the frequency of tumor recurrence.In recent years,nanomaterials mediated tumor diagnosis and therapies have been in the ascendant.How to design nanomedicines according to the characteristics of TME and improve the therapeutic effect have become hot topics in the field of nanomedicine.Based on above background,we mainly carried out following works:1.Bovine serum albumin-iridium oxide nanoparticles(BSA-IrO2 NPs)with extraordinary photothermal conversion efficiency,good photocatalytic activity,and a high X-ray absorption coefficient were prepared through one-step biomineralization.The nanoparticles allow tumor phototherapy and simultaneous photoacoustic(PA)imaging,thermal imaging and computerized tomography(CT)imaging.More importantly,BSA-IrO2 NPs have catalase(CAT)-Iike activity that could protect normal cells against H2O2-induced inflammation while significantly enhancing PA imaging through oxygen(O2)microbubble-based inertial cavitation.These remarkable features may open up the exploration of nanoparticles with precise diagnosis,effective therapy,and self-anti-inflammatory properties.2.Multi-caged IrOx nanocarriers were fabricated by direct thermal hydrolysis strategy,which could be applied into photothermal therapy(PTT),photodynamic therapy(PDT),sonodynamic therapy(SDT),outstanding gemstone spectral computed tomography(GSCT)imaging,PA imaging and drug delivery.As a proof of concept,a GSCT/PA/fluorescence imaging-guided oxygen self-sufficient sono-photochemotherapy nanoagent by simple loading of doxorubicin was constructed.The remarkable synergistic therapy and excellent hypoxia releasing capabilities could remove both subcutaneous tumor and sentinel lymph nodes metastatic tumors,and effectively suppress tumor recurrence and lung metastasis,thus greatly prolonging survival time.This study constructed a "six-in-one"(tri-modal therapies and three imaging modalities)tumor theranostic system,provided an attractive candidate of therapeutic agent.3.We found iridium oxide nanoparticles(IrOx NPs)possess acid-activated oxidase(OXD)and peroxidase(POD)-like functions and wide pH-dependent CATlike property.The integration of natural glucose oxidase(GOD)could unlock the OXD and POD-like activities of IrOx NPs by the production of gluconic acid from glucose in cancer cells,and the produced H2O2 was converted into O2 to compensate its consumption in GOD catalysis owing to the CAT-like function of the nanozyme,thus resulting in the continual consumption of glucose and the self-supply of substrates to generate superoxide anion and hydroxyl radical(·OH).Moreover,IrOx NPs could constantly consume glutathione(GSH)by self-cyclic valence alternation of IrⅣ and IrⅢ.These cascaded reactions led to "butterfly effect" of initial starvation therapy and the subsequent pressure of multiple reactive oxygen species to completely broke the self-adaption of cancer cells.4.We prepared(-)-epigallocatechin-3-o-gallate(EGCG)-molybdenum ion coordination nanoparticles(BEM NPs).Once BEM NPs were exposed to overexpressed GSH in tumor cells,they underwent a dramatic morphological change from nanodots to irregular aggregations with micron-size through Michael addition,which could mechanically disrupt endosomal and plasma membrane,inducing caspase-1 reliant pyroptosis and activating anti-tumor immunological response.Whats’more,the existence of molybdenum ions with low valence state and polyoxometalate could catalyze H2O2 to toxic ·OH and singlet oxygen(1O2)through Fenton-like reaction and Russel mechanism for boosting the overall therapeutic efficacy.Ultimately,the combination of BEM NPs and immune checkpoint inhibitors(anti-CTLA4)contributed to the versatile inhibition of different types of tumor.