Research Projects

Castration-resistant prostate cancer (CRPC) remains a major therapeutic challenge, characterized by resistance to androgen deprivation therapy and poor response to conventional chemotherapeutics. While prostate-specific membrane antigen (PSMA) has emerged as a clinically validated biomarker—overexpressed in the majority of CRPC cases—current PSMA-targeted therapies, including small-molecule radioligands and antibody-drug conjugates, are hindered by rapid systemic clearance, off-target toxicity, particularly in kidneys and salivary glands, and high production costs. These limitations underscore the urgent need for a safer, more targeted, and scalable therapeutic delivery system. This proposal aims to develop a plant-derived extracellular vesicle (EV)-based nanoplatform for PSMA-targeted, image-guided, and synergistic photodynamic and photothermal therapy (PDT/PTT) of CRPC. Plant EVs offer several advantages over synthetic and mammalian-derived carriers: they are biocompatible, low-immunogenic, and derived from sustainable, edible sources. Our preliminary work has established a robust pipeline for EV isolation from four medicinal plants—Beta vulgaris (beet), Ocimum sanctum (tulsi), Allium sativum (garlic), and Azadirachta indica (neem)—validated for morphology, size distribution, protein content, and drug-loading capacity. This builds on our published work on Catharanthus roseus-derived exosomes as nanocarriers, and a recent study on PSMA-targeted starPEG nanocarriers for CRPC imaging and therapy published in Advanced Healthcare Materials (2024), demonstrating tumor-specific delivery and translational promise. A NIR-activatable photosensitizer, PQ-TPAOC, previously synthesized and validated in-house, exhibits strong ROS generation and photothermal conversion under light exposure. This agent will be passively loaded into the isolated plant EVs. The first phase of the project involves screening all four EV types for drug loading efficiency, colloidal stability, and PDT/PTT performance, selecting the top two candidates for advanced studies. These EVs will then be surface-engineered with a PSMA-targeting ligand (ACUPA-NCS) and fluorescently labeled (5-FITC) for real-time imaging. In vitro evaluation will be carried out using PSMA-positive (LNCaP) and PSMA-negative (PC3) prostate cancer cell lines to assess targeting specificity, ROS and heat generation, and light-triggered cytotoxicity. Parallel formulations of Talazoparib-loaded EVs and free Talazoparib will be tested to directly compare phototherapy with chemotherapy. The best-performing formulation will advance to in vivo studies in a dual xenograft (LNCaP/PC3) CRPC mouse model to assess biodistribution, tumor targeting, therapeutic efficacy, and systemic safety. This project addresses critical scientific gaps in EV functionalization, targeted delivery, and phototherapeutic activation, integrating imaging, therapy, and targeting into a single, plant-derived nanocarrier. It proposes a modular, green nanomedicine platform with high translational relevance and scalability. Outcomes from this work may lay the foundation for IP generation, future clinical translation, and expansion into broader solid tumor therapies.