Development of squaraine and croconaine probes for theranostic applications

• Main Author: Ferdinandus
• Other Authors: Xing Bengang
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2025
• Subjects: Chemistry; Medicine, Health and Life Sciences; Squaraine; Croconaine
• Online Access: https://hdl.handle.net/10356/182235
• Institution: Nanyang Technological University

Squaraine (SQR) and croconaine (CRO) probes represent two distinctive classes of oxocarbon compounds characterized by their strong electron-accepting properties, thanks to their highly conjugated structure. This unique feature enables the development of probes with absorption in the far-red or near-infrared (NIR) regions. In this thesis, we delve into the synthesis of a library of SQR and CRO probes and explore their applications in theranostics. First, we investigated a library of asymmetric lipophilic SQR probes, which excel as fluorescence probes for tracking and imaging lipid droplets (LD) in their native state within cancer cells. These probes exhibited exceptional bimodal staining capabilities, targeting both LD and ER organelles through the simple diffusion of small lipophilic molecules. LD staining occurs almost instantly, while ER staining efficiency can be controlled by adjusting the probe’s lipophilicity and incubation time. Next, we explored the applications of SQR probes for antibacterial photodynamic therapy (aPDT), leveraging their capacity to generate cytotoxic Reactive Oxygen Species (ROS) upon light exposure. SQR29 was incorporated into a natural lignin hydrogel, allowing localized and targeted treatment at infected sites. Simultaneously, the hydrogel effectively scavenged free radicals to mitigate oxidative stress and promoted wound healing. Moreover, this SQR-hydrogel system demonstrated a significant aPDT effect against both Gram-negative and Gram-positive bacteria upon light irradiation, highlighting its potential in combating multidrug-resistant pathogenic bacteria in chronic wound infections. Thirdly, we developed SQR-tagged Autophagy-tethering compounds (ATTEC) designed to enhance LD degradation of LD by harnessing the endogenous lipophagy pathway. SQR22, acting as LD warhead, was paired with LC3-binding warhead 5,7-Dihydroxy-4-phenylcoumarin (DP) to attract the LC3 protein of the autophagosome. This approach using the SQR22DP construct significantly improved LD degradation, evidenced by a reduction in both the number and size of LDs in differentiated mouse fibroblasts. Finally, we introduced a novel CRO probe as a photothermal agent to enhance gene delivery through photothermal-assisted surface-mediated transfection. An organophotosensitizer (CRO32TMI) was developed to enhance the photothermal conversion efficiency of a polydopamine-polyethyleneimine (PDA-PEI) mixture. Unlike the native PDA-PEI mixture, which demands high laser power for moderate transfection efficiency and risks cell viability, the PDA-PEI-CRO32TMI construct outperformed traditional solution-based transfection reagents, Au nanoparticle, and Vanadyl naphthalocyanine, achieving superior results with minimal laser power density.