A Self-Evaluating Photothermal Therapeutic Nanoparticle

Photothermal therapy(PTT),as a very promising alternative method for cancer treatment,has attracted much attention in recent years.PTT only requires a simple non-invasive operation process,causes less damage to healthy tissues,and has strong controllability.The effectiveness of PTT depends largely on the photothermal agent.The fourth generation photothermal agent,organic dye with near-infrared(NIR)absorption,has been widely used in PTT research because of good biocompatibility,low cytotoxicity and easy degradation.However,they display critical limitations such as no tumor targeting,low photo stability,and easy renal clearance.Interestingly,formation of a NIR nanoparticle not only concentrates the NIR dye but also notably improves the photothermal conversion efficiency of the nanoparticle due to aggregation-caused quenching(ACQ)of the dye fluorescence.In the clinical,there are two molecular-level methods for post-treatment evaluation of the therapeutic effects on tumors.One is imaging evaluation with diagnostic agents and the other one is cytological and histopathological examination.However,currently,cancer therapy and imaging evaluation of its therapeutic effect are conducted separately,leading to the whole cancer-theranostic process time-consuming,tedious,and uneconomic.To achieve the purpose of evaluating therapeutic effect in time,a strategy of combination of diagnostic agents and anti-cancer drugs has been developed.For example,the combination of tumor microenvironmental indicator molecules(pH indicator molecules,oxygen content indicator molecules,etc.)with anticancer drugs achieves the feedback of treatment effect,but it is also faced with great difficulties in design and preparation.Therefore,it is imperative to develop non-invasive,highly efficient theranostic strategies which,in the meantime,are able to evaluate their cancer-therapeutic effects in real-time.In this proposal,we rationally designed and synthesized a precursor Cys(StBu)-Asp-Glu-Val-Asp-Lys(Cypate)-CBT(Cy-CBT)which contains a caspase 3 substrate DEVD and a near-infrared dye Cypate.When subjected to a CBT-Cys click condensation reaction,this precursor can be used to "smartly" and facilely prepare biocompatible,fluorescence-quenched nanoparticles.Once uptaken by tumor cells and under laser irradiation at 808 nm,these nanoparticles can be used for phtothermal tumor therapy.During photothermal therapy,tumor cells will highly express caspase 3 which in turn cleave the DEVD substrate from the nanoparticles and disassemble the nanoparticles,turning Cypate near-infrared fluorescence "On".And the "Turn-On"fluorescence can be used to evaluate the phtothermal tumor-therapeutic effect.This"smart" strategy realized the integration of photothermal tumor therapy and self-evaluation of the therapeutic effect.