Research Projects

Castration-resistant prostate cancer (CRPC) represents a clinically aggressive and therapeutically challenging stage of prostate cancer, often progressing despite androgen deprivation therapies and showing poor response to conventional chemotherapeutics. Prostate-specific membrane antigen (PSMA) is a well-validated molecular target overexpressed in most CRPC tumors. While PSMA-targeted radioligands such as 177Lu-PSMA-617 have shown promise, their clinical efficacy is often compromised by rapid clearance and off-target accumulation in PSMA-expressing healthy tissues like kidneys and salivary glands. These limitations necessitate high or repeated dosing, increasing systemic toxicity and limiting therapeutic windows. Research Questions: This project addresses the urgent need for a highly selective, image-guided therapeutic platform that minimizes off-target toxicity while retaining potent tumor ablation capability. The central research question is whether a PSMA-targeted antibody-drug conjugate (ADC), incorporating a near-infrared (NIR) photosensitizer and imaging label, can provide spatially controlled, light-activated therapy for CRPC. The working hypothesis is that combining receptor-specific targeting, synergistic photodynamic and photothermal activation, and fluorescence-based tracking within a single IgG-based ADC will enhance therapeutic precision while reducing systemic side effects. Scientific Challenges: Key challenges to be addressed include: (i) Efficient synthesis and NCS-functionalization of modular ligands (ACUPA and the NIR photosensitizer); (ii) Site-specific, multivalent conjugation to IgG without compromising stability or binding affinity; (iii) Achieving effective and synergistic PDT/PTT activation under NIR light, while maintaining photostability and avoiding aggregation. Project Overview and Novelty: This proposal aims to develop a PSMA-targeted IgG-based ADC that integrates: (1) A urea-based PSMA ligand (ACUPA-NCS) for tumor-specific delivery, (2) A triphenylamine-derived NIR photosensitizer (Ps-NCS) for synergistic PDT/PTT, and (3) Fluorescein isothiocyanate (5-FITC) for real-time imaging. This modular, light-activated design enables spatial control, multimodal synergy, and image-guided delivery—key advancements over conventional PSMA-targeted therapies. Preliminary work has already demonstrated successful synthesis of key intermediates, in-house validation of ROS and heat-generating efficacy of a prototype photosensitizer, and efficient IgG-FITC conjugation. Successful completion of this project will result in a clinically translatable theranostic platform for precision treatment of CRPC and may be extended to other PSMA-expressing tumors.