D-A-D-Type NIR-Ⅱ Small Molecules And Their Functionalized Derivatives: Design, Synthesis, And Fluorescence Imaging Applications

As a class of organic optical materials with great potential for clinical translation,NIR-Ⅱ small molecules with a donor-acceptor-donor（D-A-D）structure are widely applied in biosensing,optical imaging,and phototherapy due to their good biocompatibility,excellent chemical structural stability,and flexible optical properties.In recent years,thanks to the fast development of the noninvasive NIR-Ⅱ fluorescence imaging（FLI）technology,D-A-D-type NIR-Ⅱ small molecules have been widely used as NIR-Ⅱ fluorescent contrast agents.In addition,the intrinsic phototherapeutic properties enable them feasible for related phototherapeutic applications,such as photothermal therapy（PTT）.However,the currently reported D-A-D-type NIR-Ⅱ small molecules still have several deficiencies in structural design and imaging applications:1.The electron acceptors of D-A-D-type NIR-Ⅱ small molecules are mostly limited to benzobisthiadiazole（BBTD）;2.The imaging quality and therapeutic effect of the currently designed D-A-D-type NIR-Ⅱ small molecules are poor;3.Most of the NIR-Ⅱ small molecules developed based on the D-A-D structure face serious problems of low fluorescence quantum efficiency（QY）due to aggregation-induced quenching（ACQ）;4.The related functional derivatives based on D-A-D-type NIR-Ⅱ small molecule fluorescent contrast agents need to be further developed.Therefore,we aim to develop a series of D-A-D-type NIR-Ⅱ small molecules with high fluorescence brightness and imaging quality,expanding their related functionalized derivatives to enrich their applications in NIR-Ⅱ FLI and imaging-related therapeutic applications.The thesis can be divided into four sections:1.Design of D-A-D-Type NIR-Ⅱ Small Molecules for NIR-Ⅱ FLIIn response to the restricted acceptor selection of D-A-D-type NIR-Ⅱ small molecules,two common acceptors,thienoisoindigo（TIIG）and 6,7-bis（4-（hexyloxy）phenyl）-4,9-di-（thiophen-2-yl）-[1,2,5]thiadiazolo[3,4-g]quinoxaline（TTQ）,were selected to design and synthesize a series of D-A-D-type small molecules.Through systematic analysis of their optical properties,only TTQ-based small molecules（TTQ-Xs）exhibit obvious NIR-Ⅱ fluorescence signal.This proves that TTQ is a suitable acceptor for designing D-A-D-type NIR-Ⅱ small molecules,which also expands their molecular library.2.Molecular Planarity-Based Donor/Side Chain Engineering for NIR-Ⅱ PhototheranosticsIn response to the poor imaging and therapeutic effects of D-A-D-type NIR-Ⅱ small molecules,a simple yet clear strategy based on molecular planarity was proposed to modulate their molecular planarity.Bulky planar units and terminal alkyl side-chains are grafted to the central D-A-D core to enhance the coplanarity of the targeted molecules.The resulting BETA NPs with optimized molecular planarity displayed a remarkably high molar extinction coefficient at 1064 nm(1.13×10⁴ M^-1 cm^-1),which enables an enhanced NIR-Ⅱa（1300-1400 nm）fluorescence to realize a clear NIR-Ⅱa FLI.More importantly,an ultrashort-lived femtosecond component（79 fs）was observed in femtosecond transient absorption spectra to identify the unbeatable NIR-Ⅱ photothermal conversion efficiency（47.6%）of BETA NPs.Finally,the efficient NIR-Ⅱ phototheranostics of BETA NPs was successfully demonstrated in 4T1 tumor-bearing mice.3.Starlike Polymer Brush-Based Ultrasmall Nanoparticles for Brain Tunor ImagingIn response to the inherent hydrophobicity and low QY of D-A-D-type NIR-Ⅱ small molecules,the starlike polymer brush-based ultrasmall（～8 nm）nanoparticles with ultra-small particle size（～8nm）were developed.First,a small-molecule-based chain transfer agent（TQF-CTA）capable of reversible addition-fragmentation chain transfer（RAFT）polymerization was synthesized.And then four dense and hydrophilic oligo（ethylene glycol）methyl ether methacrylate（OEGMA）were grafted onto the four branches of TQF-CTA,which minimizes the strong aggregation between the core hydrophobic dyes,protecting them from strongπ-πinteractions with each other.TQFP-10 NPs thus exhibit good water solubility,bright NIR-Ⅱ fluorescence（QY=1.9%）,long blood circulation half-life(t_1/2=8.5 h)and enhanced tumor accumulation ability for efficient brain tumor（GBM）imaging.4.Design and Biological Application of D-A-D-Type NIR-Ⅱ Small Molecular Functionalized DerivativesIn response to the slow development of D-A-D-type NIR-Ⅱ small molecular functional derivatices,combined with previous work experience,three copolymers with different functions were successfully prepared by RAFT polymerization using OEGMA,styrene,or N-isopropylacrylamide（NIPAAm）as monomer and TQF-CTA as chain transfer agent.Their corresponding nanoparticles,such as TQF-P（S-co-OEGMA）NPs with fluorescence-enhancing ability,TQFPNs with inflammation-targeting ability,and TPNO NPs with thermosensitiveenhancing fluorescence,greatly facilitate their applications in biomedicine.