Research On Synthesis And Properties Of BODIPY Probes For Tumor Microenvironment

Tumor and cancer are the most fatal killers that threaten all humans’life and health. For detection and treatment of tumor cells and tissues, fluorescence imaging and photodynamic therapy (PDT) are often involved. Here we built up two BODIPY-related probes for tumor hypoxia and tumor acidity, two remarkable characteristics of tumor microenvironment.We firstly constructed a fluorescent probe (Hyp-Ly) for specifically imaging lysosome in hypoxic tumor cells. Such probe was designed to integrate azobenzene moiety and BODIPY chromophore into one system by a piperazine linker. Here, the azobenzene unit serves as both a specific target for a hypoxia-related enzyme azoreductase and a strong BODIPY fluorescence quencher. In the presence of azoreductase, the azobenzene bond is reductively cleaved to generate an aminobenzyl carbamate, followed by self-immolation to liberate piperazine modified BODIPY (BOD-Ly). Interestingly, BOD-Ly possesses acidic pH protonation feature, and thus mostly localizes within the acidic environment of lysosome. Consequently, Hyp-Ly fulfills the lysosome targetable function and gives dramatic fluorescence enhancement in hypoxic tumor microenvironment, providing a specificity of visualizing lysosome in hypoxic tumor cells.We also designed and synthesized a polymer-based PDT photosentisizer PDPA-AMA-BOD. To construct PDPA-AMA-BOD, an amphiphilic polymer PDPA-AMA was initially synthesized, and then an iodine-substituted BODIPY photosentisizer was covalently tethered to the hydrophobic end of PDPA-AMA, which can generate cytotoxic singlet oxygen under the excitation of light. PDPA-AMA-BOD can self-assemble into micelles in neutral aqueous environment and entrap the BODIPY photosentisizer within the hydrophobic interior, making the local concentrations of BODIPY to be high. Such effect decreases the efficiency of 1O2 generation by homo-FRET effect upon excitation. In contrast, the protonation of amino sites on the hydrophobic end of PDPA-AMA-BOD can destroy the micelles’ structure and enable the polymer well-dispersible in acidic aqueous solutions. As a consequence, concentration induced inhibition of 1O2 production was abolished. In this way, PDPA-AMA-BOD is an acidity-sensitive PDT photosentisizer, which shows a higher therapeutic effect upon tumor cells under acidic conditions. Experimental results proved the acidity-controlled production of 1O2, inferring the potential application as a selective PDT photosentisizer towards acidic tumor microenvironment.