Rational Design of Functional Photosensitizers and Photothermal Agents for Imaging-guided Cancer Phototherapy

Abstract

Phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), has emerged as a promising theranostic approach with several advantages including spatial-temporal controllability, non-invasiveness and negligible drug-resistance. As the crucial elements for phototherapy, the development of innovative photothermal agents (PTTAs) and photosensitizers (PSs) with distinguished properties has been receiving sustained attention. Especially, substantial efforts have been focused on developing PTTAs with high PTT efficiency, tumor targeting ability, and PSs with high ¹O₂ production efficiency, organelle-targeting ability and red to near-infrared (NIR) absorption. Additionally, activatable PTTAs and PSs triggered by specific targets could enhance tumor-targeting ability, thereby minimizing damage to normal tissues. The main objective of this dissertation is to design functional PTTAs and PSs with the aforementioned properties, which could be utilized in imaging guided phototherapy.

Chapter 1 offers an in-depth summary of phototherapy, including PTT and PDT, focusing on design strategies for enhanced PTT targeting, bio-responsive PTTAs, and advanced PSs with high ¹O₂ production, organelle targeting, and red to NIR absorption, along with activatable PSs.

Chapter 2 describes the successful development of B-CDX, a self-assembling, cancer-targeting photothermal agent derived from a small near-infrared fluorescent (NIRF) dye, Hemicyanine. Extensive investigation into B-CDX’ PTT efficiency in cancer cells revealed its exceptional specificity in uptake and elucidated the molecular mechanisms of induced cell death, primarily through mitochondrial apoptosis pathways. Furthermore, B-CDX demonstrated significant photoacoustic signaling capabilities, confirmed by both in vitro and in vivo studies. This probe’s high PTT efficacy with high stability, biosafety, and ability to provide high-resolution photoacoustic imaging in the NIR-I window underscore its potential in precise tumor visualization and targeted phototherapy.

Chapter 3 details the synthesis and development of B-SQ, a self-assembling, cancer-targeting, activatable photosensitizer, engineered from a small NIRF dye, Squaraine. We comprehensively evaluated B-SQ’s PDT efficacy in cancer cell models. B-SQ exhibited notable cancer cell specificity, with its PDT effectiveness being activatable and distinguishable by NIR fluorescence. This research marks the first demonstration of B-SQ inducing both apoptosis and cell cycle arrest in cancer cells through PDT.

Chapter 4 presents the development of MB-NBSe, a multifunctional probe designed for biothiol discrimination and targeted cancer PDT. Exhibiting rapid reaction kinetics, high sensitivity, and selectivity towards biothiols in aqueous buffers, MB-NBSe leverages a tri-channel fluorescence strategy to provide four absorption outputs and three fluorescence channels, each tailored to H2S, Cys/Hcy, and GSH. Capable of visualizing exogenous biothiols in cells, MB-NBSe effectively distinguishes between cancerous and normal cells. Its potent PDT efficacy, targeting and eliminating cancer cells, positions MB-NBSe as a notable advancement in biothiol detection and cancer treatment.

Chapter 5 summarizes the dissertation, highlighting limitations in current PTTAs and PSs for phototherapy. It emphasizes the need for future research on PTTAs with enhanced targeting, and PSs with high ¹O₂ yield, red to NIR absorption, and organelle-targeting capabilities, and developing activatable PTTAs and PSs.

Date of Award	29 Apr 2024
Original language	English
Awarding Institution	City University of Hong Kong
Supervisor	Hongyan SUN (Supervisor) & Chun Kit KWOK (Co-supervisor)