Design,syntheses,and Phototheranostic Applications Of Conjugated Small Molecule Nanoagents

Cancer has become the leading cause of human's death worldwide.Although conventional therapies,such as surgery,chemotherapy,and radiotherapy have been widely applied in clinics,they suffer from several disadvantages,including invasiveness,substantial side effects,and lacking targeting.In recent years,photothermal therapy?PTT?and photodynamic therapy?PDT?based on nanomaterials and near-infrared?NIR?laser have received increasing attention due to their noninvasiveness,few side effects,and remote-controllability.Moreover,because of the strong radiative relaxation and nonradiative relaxation of these nanomaterials,they can also be used in fluorescence imaging?FLI?and photoacoustic imaging?PAI?.With excellent imaging and therapeutic outcome,phototheranostic nanomaterials have great potential in tumor phototheranostics.To date,numerous phototheranostic nanomaterials have been developed,such as noble metal nanomaterials,transition metal nanomaterials,carbon-based nanomaterials,and conjugated polymer nanoparticles?CPNs?.However,the long-term toxicity caused by non-biodegradable inorganic nanomaterials and batch-dependent optical properties of polymeric nanomaterials severely hinder their clinical translation.Therefore,developing highly efficient chemically defined conjugated small molecules?CSMs?-based phototheranostic nanomaterials is of great significance for the large-scale preparation and clinical translation of phototheranostic agents.In this thesis,we firstly synthesized three donor-acceptor-donor?D-A-D?CSMs?CSM0-2?withtriphenylamine?TPA?asdonorand benzo[1,2-c:4,5-c']bis?[1,2,5]thiadiazole??BBT?as acceptor.With the number of thiophene?Th?bridges increasing from 0 to 2,the photo-responsivity undergoes a transition from NIR-I?650-950 nm?of CSM0 to NIR-II?1000-1700 nm?of CSM2.The effect of the number of thiophene bridges on the optical properties of the CSMs is demonstrated by density functional theory?DFT?calculation.Water-soluble conjugated small molecule nanoparticles?CSMN0-2?were prepared by a nanoprecipitation method and the photothermal conversion efficiency?PTCE?of CSMN0-2 increases with the number of thiophene bridges increasing from 0 to 2 in both NIR-I and NIR-II.With a high PTCE?31.6%?in NIR-II and good biocompatibility,CSMN2 was successfully applied in PAI-guided NIR-II deep-tissue PTT.In the second part,through acceptor-oriented molecular design,we synthesized a D-A-D CSM?IID-Th TPA?with TPA as donor and isoindigo?IID?as acceptor and prepared IID-Th TPA NPs.IID-Th TPA NPs exhibit strong NIR absorption,high PTCE?35.4%?,and ultrahigh singlet oxygen quantum yield??_?=84.0%?.The ultrahigh singlet oxygen quantum yield of IID-Th TPA NPs originates from the narrow lowest excited singlet state-lowest excited triplet state energy gap(?E_ST=0.65 e V)as revealed by DFT calculation.Based on the high PTCE,?_?,and excellent biocompatibility,IID-Th TPA NPs were successfully applied in PAI-guided synergistic PTT/PDT.We have synthesized a series of D-A-D CSMs via molecular engineering,affording a highly efficient NIR-II phototheranostic agent of CSMN2 and a phototheranostic agent of IID-Th TPA NPs capable of synergistic PTT/PDT.Our work will shed more light on the structure-property relationship of CSMs and CSMNs and establish guidelines for the development of next-generation highly efficient CSMs-based phototheranostic nanoagents.