Tröger’s Base as a Potential Bridge to Type‑I Photosensitizers: Mechanism and Antitumor Applications

In contrast to Type-II photodynamic therapy (PDT), Type-I
PDT with
less oxygen consumption has shown great potential against tumor hypoxia.
However, there are limited strategies available for designing Type-I
photosensitizers (PSs). Herein, we present a promising strategy for
synthesizing Type-I PSs (TBC-1–TBC-4) using Tröger’s
base (TB) framework. The TB framework can promote intersystem crossing
efficiency and create an electron-rich environment, making it the
most likely site for electron transfer to O2 to generate
Type-I ROS. As anticipated, TBC-1–TBC-4 demonstrates
Type-I ROS generation capability and their impressive visible light-harvesting
ability significantly enhances this capability. Among them, TBC-1 demonstrates outstanding biocompatibility and PDT efficiency
in vitro under both normoxia and hypoxia. Furthermore, TBC-1 effectively inhibits tumor growth in vivo, with negligible side
effects. This is attributed to TBC-1’s efficient
generation of Type-I ROS and endoplasmic reticulum targeting ability.
This study thus offers useful insights into developing Type-I PSs.