Development of 5D3 mAb and USPIO-Based Theranostics for Image-Guided Prostate Cancer Therapy
Abstract
Prostate cancer is the most common cancer in men after skin cancer. More than 30% of patients diagnosed die of this devastating disease. Surgery, radiation, and hormone deprivation therapy are typically used to treat prostate cancer. Since almost all invasive prostate cancers eventually become castrate-resistant prostate cancer (CRPC) and metastasize, chemotherapeutics are also important for control of the disease. However, commonly used drugs, such as docetaxel and cabazitaxel, have a low therapeutic efficacy and cause severe side effects. To fill the gap, novel, image-guided, targeted and effective therapeutics are urgently needed. In this project, our objective is to develop a highly efficacious drug delivery system with minimal side effects based on a nanocarrier, an antibody, and chemotherapeutics with unique properties to address the overarching challenges of the Department of Defense, Prostate Cancer Research Program to (1) improve the quality of life for survivors of prostate cancer and (2) develop treatments that improve outcomes for men with lethal prostate cancer. Almost all aggressive prostate cancers overexpress prostate-specific membrane antigen (PSMA), and we target PSMA to deliver the drug to cancer cells. We will use a new PSMA-targeting 5D3 antibody in this drug delivery system. This antibody has higher binding capabilities with PSMA than other existing PSMA-targeting antibodies. Ultra-small superparamagnetic iron oxide (USPIO) nanoparticles are biocompatible and have a high loading capacity for molecules. Since USPIO is an MRI contrast agent, drug delivery and tumor uptake can be detected with MRI. We have ‘decorated’ the surface of the USPIO with a PSMA-specific 5D3 monoclonal antibody. This complex will be loaded with mertansine (DM1), an anti-tubulin drug molecule. These drug delivery systems are called nano-theranostics since this system has both therapeutic and image-guided diagnostic capabilities. Our specific aims are to synthesize, characterize, and test this new system in prostate cancer cells and mouse models of human prostate cancer. Novel PET-MRI imaging will be used to evaluate the drug delivery to the tumor and early tumor response to the therapy. The proposed studies build on a strong foundation to develop a highly effective and non-invasive image-guided drug delivery system, using biocompatible high capacity USPIO nanoparticles, to treat PSMA-overexpressing prostate cancer. This project is designed for 3 years as phase “zero” research. If successful, at the end of the 3-year period, we will have optimal drug/delivery system candidates to proceed to experimental clinical research in patients. Phase I/II/III stages typically require in the range of 2 to 10 years (average, 5 years). The review and approval from the National Drug Administration takes approximately 2 years. Therefore, the total time that would be required to achieve the post-marketing surveillance is approximately 10 years. However, intellectual discoveries, methodology, and technologies developed as a result of the proposed project will be disseminated in the medical research community throughout the project, thus helping fellow researchers in the field to help with in-progress or future discoveries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010429
Entities
People
- Sudath Hapuarachchige
Organizations
- Johns Hopkins University
- United States Army