β-Ionic Conjugated Chlorin-Type Photosensitizers Based on Porpholactone: Synthesis, Photophysical Properties, and Photodynamic Activity

Porpholactones and their derivatives have attracted increasing attention for their promising application as photosensitizers. Reduction of the beta-lactone moiety in porpholactone to beta-hemiacetal, named porpholactol, allows the synthesis of chlorin-type photosensitizers with enhanced near-infrared absorption as well as beta functionalization of water-soluble conjugates. By employing beta-hydrophilic conjugates terminated by different ionic groups, such as neutral (ZnL1), anionic (ZnL2), zwitterionic (ZnL3), and cationic (ZnL4-6) groups, a series of photosensitizers (ZnL1-6) were synthesized and characterized, and their photophysical properties were studied, including magnetic circular dichroism measurement. The terminal ionic groups on beta conjugates influence significantly the cellular uptake of ZnL1-6 in the order ZnL4-6 (positive charge) > ZnL1-3 (negative charge or neutral). Importantly, the photocytotoxicity of ZnL1-6 against cancer cells showed IC50 values down to the sub-micromolar range and exhibited the same trend as their cellular uptake, clearly revealing the relationship of beta-ionic conjugates, cellular uptake, and intracellular photodynamic therapy (PDT) activity. Furthermore, using ZnL4 as an example, mechanistic studies, such as cell imaging experiments and Western blot analysis for the PDT process, indicate that ZnL4 exerts photodynamic activity through apoptosis, which is highly associated with lysosome disruption, mitochondria depolarization, and nuclei condensation.