Rational Design of Functional Photosensitizers for Imaging-guided Photodynamic Therapy

Abstract

Photodynamic therapy (PDT) has emerged as a promising theranostic approach with several advantages including spatial-temporal controllability, non-invasiveness and negligible drug-resistance. As a crucial element for PDT, the development of innovative photosensitizers (PSs) with distinguished properties has been receiving sustained attention. Especially, substantial efforts have been focused on developing PSs with high 1O2 production efficiency, organelle-targeting ability and red to near-infrared (NIR) absorption. Additionally, activatable PSs triggered by specific targets could achieve site-specific PDT, thereby minimizing damage to normal tissues.

The main objective of this dissertation is to design functional PSs with the aforementioned properties, which could be utilized in imaging guided PDT. Chapter 1 provides a detailed introduction to PDT, with a focus on the design strategies of PSs with properties such as high ¹O₂ production efficiency, organelle targeting ability and red to NIR absorption. Additionally, representative activatable PSs are introduced.

In chapter 2, an activatable PS originated from methylene blue (MB) that could be activated by β-gal was constructed. Initially, absorption as well as fluorescence of PS MB-βgal was suppressed, along with inhibited PDT efficiency. In the presence of β-gal, absorption and fluorescence of MB-βgal were restored. Meanwhile, a much higher PDT efficiency was accomplished upon treatment of β-gal. Furthermore, recuperative fluorescence was used to visualize senescent cells with overexpressed β-gal and corresponding PDT effect was employed to ablate these senescent cells effectively.

In chapter 3, two molecular rotor-based PSs were reported, which could achieve mitochondrial-targeted PDT and synchronously indicate fluctuations of mitochondrial viscosity during PDT process. With the aid of such kind of dual functional PSs, we could shed light on the dynamic changes of mitochondrial viscosity during PDT and further guide the PDT process. Furthermore, it’s worth highlighting that absorption of PS CCVJ-Mito-2 was in the NIR region, which is suitable for clinical applications.

In chapter 4, we constructed two self-reporting PSs that could achieve membrane-targeted PDT and provide feedback of the phototherapeutic effect with fluorescence signal readout. Specifically, MRMP-1/2 is rotor-based molecule whose fluorescence would be enhanced in a highly viscous environment. Meanwhile, they could act as PSs which could generate ¹O₂ under specific irradiation condition. Thus, the two PSs could ‘light up’ the plasma membrane after inserting into it. Likewise, their fluorescence would be suppressed once the membrane was disrupted during the PDT process. Therefore, they are two membrane-targeted self-reporting PSs, which hold great potential in the application of imaging-guided PDT. It is worth highlighting that absorption of MRMP-2 is in the NIR region, which is suitable for clinical application, and relevant studies are underway.

Finally, chapter 5 provides a brief summary of this dissertation, by pointing out common drawbacks of current PSs for PDT applications. Meanwhile, it highlights that sustained future efforts should be focused on designing PSs regarding high ¹O₂ quantum yield, red to NIR absorption and organelle-targeting capability. In addition, designing activatable PSs to avoid side effects towards normal tissues is another research orientation. Finally, it remains a challenging but very meaningful topic to improve the performance of PSs in hypoxic tumor environment.

Date of Award	13 Jun 2023
Original language	English
Awarding Institution	City University of Hong Kong
Supervisor	Hongyan SUN (Supervisor)