Development And Application Exploration Of Clearable Inorganic Photothermal Nanoagents

Photothermal therapy（PTT）,as an emerging therapy strategy of tumor and bacterial infections,has been receiving increasing attention.Photothermal nanotherapy which utilizes hyperthermia generated from absorbed near-infrared（NIR）light by photothermal nanoagents to kill tumor or bacterial cells is application wide,noninvasive,highly selective,process simple,and damage less to normal tissues.Recent years have witnessed an ever-growing passion into research of photothermal nanoagents.Among them,inorganic photothermal nanoagents,with various compositions,adjustable structures and controlled morphologies,ensure excellent photothermal performance;simultaneously,they represent electrical,optical,acoustic,magnetic and thermal properties,etc.beneficial for bioimaging and multifunctionalization to detect and combat tumor or bacterial infections.More importantly,inorganic nanomaterials could often passively accumulate in tumors or infection sites with higher concentrations and longer retention time through the enhanced permeability and retention effect for tumor or penetrable blood vessels in bacterial infection sites（passive targeting）,respectively,which enables precise antitumor or antibacterial therapy.Although various inorganic photothermal nanoagents have recently sprung up for photothermal antitumor or antibacterial application,however,their actual clinical practice is still very limited thus far.The most worrisome problem as for inorganic photothermal nanoagents has been their biosafety.Larger inorganic nanomaterials with the innate non-biodegradable nature would accumulate in the reticuloendothelial systems such as liver and spleen,and inevitably give rise to long-term toxicity,inflammatory response,or even fibrosis and cancer.Hence,developing clearable inorganic photothermal nanoagents is of vital significance for clinical translation of inorganic photothermal nanoagents.The development of clearable inorganic photothermal nanoagents is in the ascendant.Up till now,different kinds of clearable inorganic photothermal nanoagents have appeared.Nevertheless,such reported clearable inorganic photothermal nanoagents mostly require complicated synthesis procedure,have dissatisfied photothermal performance and single function,and are confined in antitumor realm.Consequently,it is highly desirable to explore clearable inorganic photothermal nanoagents with simple synthetic process,favorable biosafety as well as excellent photothermal performance,and extend their function and application field.In this thesis,related work was carried out as listed below:（1）Degradable rhenium trioxide（ReO₃）nanocubes（NCs）with high localized surface plasmon resonance absorbance like gold for photothermal theranosticsThe applications of inorganic theranostic agents in clinical trials are generally limited to their innate nonbiodegradability and potential long-term biotoxicity.To address this problem,herein via a straightforward and tailored space-confined on-substrate route,we obtained ReO₃ NCs that display a good biocompatibility and biosafety.Importantly,their aqueous dispersion has high localized surface plasmon resonance absorbance in NIR region different from previous report,which possibly associates with the charge transfer and structural distortion in hydrogen rhenium bronze（H_xReO₃）,as well as ReO₃’s cubic shape.Such a high localized surface plasmon resonance absorbance in the NIR region endows them with photoacoustic（PA）/infrared（IR）thermal imaging,and high photothermal conversion efficiency（⁵7.0%）for efficient ablation of cancer cells.Also,ReO₃ NCs show X-ray computed tomography（CT）imaging derived from the high-Z element Re.More attractively,those ReO₃ NCs,with pH-dependent oxidized degradation behaviors,are revealed to be relatively stable in hypoxic and weakly acidic microenvironment of tumor for imaging and treatment whilst degradable in normal physiological environments of organs to enable effective clearance.In spite of their degradability,ReO₃ NCs still possess tumor targeting capabilities.We thus develop a simple but powerful,safe and biodegradable inorganic theranostic platform to achieve PA/CT/IR imaging-guided cancer PTT for improved therapeutic efficacy and decreased toxic side effects.（2）A new strategy for specific eradication of implant-related infections based on special and selective degradability of ReO₃ NCsThe greatest bottleneck for photothermal antibacterial therapy could be the difficulty in heating the infection site directly and specifically to avoid the undesirable damage for surrounding healthy tissues.In recent years the infectious microenvironments（IMEs）have been being more and more recognized as a crucial contributor to bacterial infections.Here,based on the unique IMEs and ReO₃ NCs,a new specific photothermal antibacterial strategy is reported.These NCs synthesized by a rapid and straightforward space confined on-substrate approach have good biocompatibility and exhibit efficient photothermal antibacterial ability.Especially when they are utilized in anti-biofilm,the expression levels of biofilm-related genes（icaA,fnbA,atlE and sarA for Staphylococcus aureus）can be effectively inhibited to prevent bacterial adhesion and biofilm formation.Importantly,the ReO₃ NCs can transform into hydrogen rhenium bronze（H_x ReO₃）in an aqueous environment,making them relatively stable within the low pH of IMEs for PTT,while rapidly degradable within the surrounding healthy tissues to decrease photothermal damage.Note that in phosphate buffered saline（PBS）with pH 7.4 without any assistant condition,these ReO₃ NCs have the fastest degradation rate amongst all known degradable inorganic photothermal nanoagents.This special and IMEs-sensitive selective degradability of the ReO₃ NCs not only facilitates safe,efficient and specific elimination of implant-related infections,but also enables effective body clearance after therapy.Solely containing the element（Re）whose atomic number is higher than clinic-applied iodine in all reported degradable inorganic photothermal nanoagents under PBS（pH 7.4）without any assistant condition,the ReO₃ NCs with high X-ray attenuation ability could be further applied to CT imaging-guided therapy of implant-related infections.The present work described here is the first to adopt degradable inorganic photothermal nanoagents to achieve specific antibacterial therapy and inspires other therapy on this concept.（3）An easy-to-fabricate clearable CuS superstructure-based multifunctional theranostic platform for efficient imaging guided chemo-photothermal therapyDespite drug delivery systems receiving ever-increasing attention,development of a simple,effective,sensitive and clearable drug delivery and multifunctional theranostic nanoplatform for cancer therapy is still highly desirable and remains a challenge.Herein,using a one-step solvothermal method,hollow acanthosphere-like CuS superstructures assembled from¹0 nm nanoparticles were successfully obtained and used as an efficient drug delivery and theranostic platform for PA and IR thermal imaging-guided cancer combination therapy.The special hollow characteristic of CuS superstructures with mesoporous shells and large cavities grants them high drug loading capacity;they demonstrate NIR/pH stimuli-sensitive drug release and pronounced synergetic effects of chemo-photothermal therapy both in vitro and in vivo.In particular,our as-fabricated hollow loose CuS superstructures,with easily breakable characteristic,are biodegradable and able to be cleared from the body when their therapy task is completed.This CuS-superstructure-based clearable drug delivery and“all-in-one”cancer theranostic platform might provide possibilities for improving therapeutic efficacy and minimizing adverse effects.