Design and Application of Thermally Activated Delayed Fluorescent Materials for Photodynamic Therapy


Student thesis: Doctoral Thesis

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Award date2 Sep 2021


Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. Photodynamic therapy (PDT) is an emerging therapeutic method for its merits including non-invasiveness, high-selectivity and anti-multidrug resistance. Currently, thermally activated delayed fluorescent (TADF) materials show great potential in PDT owing to their intrinsic small singlet-triplet energy gap (ΔEST), which facilitates intersystem crossing (ISC) process and increases yields of reactive oxygen species (ROS) with the presence of oxygen. This thesis mainly focuses on the design, development and application of TADF materials for PDT.

Firstly, two TADF molecules (PT and AT) with different electron-donating segments are rationally designed for manipulation of energy utilization of their excited states. By rationally changing the electron-donating sections PT and AT can effectively regulate the ΔEST and oscillator strength (f), which further tune energy flow between reactive oxygen sensitization and fluorescence emission. A small ΔEST and a small f of PT are favorable for PDT due to its efficient ISC process. In contrast, a larger ΔEST and f of AT are found to be beneficial for fluorescence imaging due to suppression of the ISC process. Such tunability enables the proposed TADF materials to exhibit tailored balances between singlet oxygen (1O2) generation and fluorescence emission. A two-photon infrared laser with great permeability is also used to excite the TADF materials for theranostic performance in vitro. These results demonstrate that TADF materials can be rationally designed as superior candidates for nanotheranostic agents by manipulating the ΔEST, and propose an effective design strategy for balancing ROS generation and fluorescence emission.

Secondly, a highly-efficient photosensitizer (PS) with notably enhanced 1O2 generation was successfully developed by introducing the heavy-atom effect into a TADF molecule. In this study, two TADF molecules, AQCz and its Br substitution AQCzBr2, with the same small ΔESTs of 0.11 eV were designed and synthesized. AQCzBr2 shows a spin-orbital coupling constant which is almost 3 times larger than that of AQCz due to the heavy-atom effect (HAE). An inert amphiphilic copolymer DSPE-PEG 2000 was incorporated for co-assembling the two molecules into water-dispersible and biocompatible nanoparticles (NPs). 1O2 quantum yield of the AQCzBr2 NPs was investigated and it is much higher than that of the AQCz NPs (0.91 vs. 0.21). The AQCzBr2 NPs are demonstrated as a safe and powerful PDT agent both in vitro and in vivo. All results suggested that applying the HAE to a TADF PS with intrinsically small ΔEST would be an effective design strategy for highly efficient PSs and providing an important perspective to invent future PSs with full potential.

Thirdly, to address the issue of low efficacy of typical type II PDT agents in solid tumors with hypoxia, a type I PDT agent (AQPO) was designed and synthesized using a typical TADF template, which ensures its small ΔEST as 0.09 eV and guarantees sufficient formation of triplet excitons. By introducing two electron-rich groups (benzyloxy) on both sides of AQPO, the electron-transfer process is greatly promoted under irradiation, leading to the generation of oxygenated radicals (e.g., O2•− and •OH) for type Ⅰ PDT. Meanwhile, the aggregation-induced emission (AIE) feature of AQPO is realized by its twisted structure, which significantly suppresses intramolecular motion and aggregation-caused quenching (ACQ) effect in aggregates. After encapsulated into an inert amphiphilic copolymer DSPE-PEG 2000, the as-prepared AQPO NP exhibits effective production of superoxide anion radical (O2•−) and hydroxyl radicals (•OH) in both normoxia and hypoxia environments and achieves an excellent anti-tumor effect in vivo, indicating its good potential as an innovative type I TADF PS.