Final Defense: Nooshin Mesbahi

About the event

Speaker: Nooshin Mesbahi

Host: Dr. Cliff Berkman

Title: DEVELOPMENT OF PSMA-TARGETED CONJUGATES FOR IN VITRO IMAGING APPLICATIONS OF PROSTATE CANCER CELLS

Abstract:

Prostate cancer is the third leading cause of cancer-related fatalities among men in the United States. While considerable progress has been made in treatment modalities, issues such as off-target toxicity and insufficient selectivity remain formidable barriers to achieving optimal therapeutic outcomes. Traditional interventions, including surgery, radiation, and hormone therapy are often associated with limited precision, inadvertently affecting non-cancerous tissues and reducing patients’ quality of life.

In response to these limitations, the field of precision oncology has pivoted toward the design of molecularly targeted diagnostic and therapeutic strategies. Among the most promising advancements is the targeting of Prostate-Specific Membrane Antigen (PSMA), a type II transmembrane glycoprotein highly expressed on prostate cancer cells. Its restricted expression in malignant prostate tissues, including both primary and metastatic lesions, positions PSMA as an ideal biomarker for selective tumor imaging and therapeutic targeting.

PSMA-targeted imaging has significantly enhanced early detection, staging accuracy, and treatment monitoring in prostate cancer. Clinically approved radiotracers, such as Gallium-68 PSMA-11 and Pylarify™, have demonstrated remarkable specificity and sensitivity in PET imaging, setting a benchmark for non-invasive prostate cancer diagnostics. The clinical success of these imaging agents has catalyzed the development of PSMA-targeted radioligand therapies like Pluvicto™ (Lu-177-PSMA-617), which uses the same targeting principle to deliver cytotoxic radionuclides directly to malignant tissues.

Despite the efficacy of radiopharmaceuticals, there is increasing interest in broadening the scope of PSMA-targeted modalities to encompass small-molecule drug conjugates (SMDCs). These conjugates are engineered to selectively deliver chemotherapeutic payloads to PSMA-expressing cells, enhancing therapeutic index while minimizing collateral damage to healthy tissues. Achieving this requires a deep mechanistic understanding of ligand-receptor interactions, intracellular uptake pathways, trafficking dynamics, and the precise site of payload release.

To this end, our research leverages fluorescent imaging agents as functional surrogates for chemotherapeutic payloads. These agents enable detailed in vitro visualization of key steps such as PSMA binding, internalization, and compartment-specific release. Central to our approach is the development of phosphoramidate-based linker scaffolds that are pH-sensitive and capable of releasing their cargo specifically within acidic endosomal and lysosomal environments. These intelligent linker systems not only emulate the behavior of cytotoxic agents but also provide a real-time readout through turn-on fluorescent dyes, serving as powerful tools for evaluating the feasibility and kinetics of intracellular delivery.

In summary, this work establishes a scientific foundation for the imaging-enabled development of PSMA-targeted drug delivery systems. The insights derived herein aim to inform the next generation of SMDCs and precision therapeutics, offering promising avenues for improving the treatment landscape for prostate cancer.