Design,Synthesis And Application Of Benzo[a]phenoxazine-Based Dyes For Cancer Imaging And Photodynamic Therapy

Benzo[a]phenoxazine-based dyes have great potential application in many fields,such as environmental sensing,biosensing and bioimaging,antimicrobial and anticancer therapy,and so forth.This thesis focuses on the design,synthesis,properties evaluation,biological imaging and photodynamic therapy application of benzo[a]phenoxazine-based molecular probes.(1)Hypoxia.inadequate oxygen supply in the body,plays an important role in tumor development and metastasis,and can also induce drug resistance.To investigate the degree of hypoxia in solid tumors,a red-emission hypoxic-sensitive two-photon(TP)fluorescent probe NRP developed by conjugating a benzo[a]phenoxazinones scaffold with p-ntrohenzyl moiety as nitroreductase(NTR)recognition unit for hypoxia imaging.NRP exhibited both one-photon and TP excited strong red-fluorescence emission in hypoxic tumor cells with?45 fold enhancement.The probe NRP is applied for monitoring of degree of hypoxia both in liver tissue slices and in vivo.(2)Tumor cell specific and organelle-localized dual-targeted PDT agents can rapidly damage the organelle function and improve therapeutic efficacy under NIR light sensitization.Lysosome is an attractive target for developing novel PDT photosensitizer,as it is a key degenerative organelle in the cell.Se-Biotin is a novel tumor cell specific and lysosome dual-targeted NIR photosensitizer designed directly by coupling the biotin-receptor molecule with benzo[a]phenoselenazinium dye(NBSe-C6-NH2)for killing malignant tumors in situ.Se-Biotin exhibited excellent cancer cell discrimination from normal cells in a co-culture model of MCF-7 and COS-7 cells,and the therapeutic PDT effect(IC50=85 nM)was associated with its lysosomal-targeting ability.Therefore,these result demonstrated that Se-Biotin will be a promising PDT agent for development of novel tumor cell specific and lysosome dual-targeted photoscnsitizer for improving antitumor effects.(3)Site-specific photodynamic therapy(PDT)is still the main challenge in the modern medicine,in particularly;selective destruction of hypoxic tumor cells remains signigicant issue in clinical application.Se-PDT was designed by introducing 4-nitrobenzyl group into the benzo[a]phenoselenazinium derivative NIR photosensitizer via carbamate linkage.Se-PDT exhibited very low quantum yield(?=0.03)and a blue-shift of absorption(580 nm).The NTR-triggered activation of Se-PDT results a release of NBSe and in drastic recovery of 1O2 generation upon photoirradiation(?=0.56)and red-shifting absorption.The Se-PDT was also activated by NTR-induced mild hypoxic tumor cells and shows excellent photosensitivity ability.The Se-PDT-treated mice were also showed significant tumor growth inhibition under irradiation.This simple NTR-based activation strategy might hold a great promise for improving of clinical PDT exists and future of new PDT design.