Rational Engineering of Designer Nanoparticles to Target Multiple Myeloma
Abstract
Multiple myeloma (MM) is caused by the proliferation of plasma cells (a specific type of blood cells) in the bone marrow (BM). The Institute of Medicine of the National Academy of Sciences concluded in 1994 that there is an association between MM incidence and exposure to Agent Orange used in Vietnam. Unfortunately, MM is still incurable due to development of drug resistance, at least in part, caused by the survival advantages provided by the BM microenvironment. Adhesion of MM cells to the BM via VLA-4 (a unique protein on MM cell surface) results in cell-adhesion-mediated drug resistance (CAM-DR). As a result, the MM cells in the BM environment are much less sensitive to effective therapeutics such as doxorubicin (Dox) and bortezomib (Bort). Hence, VLA-4 is an attractive target, both for selective targeting of MM cells, and for inhibition of CAM-DR. Nanotechnology has been recognized as a paradigm-changing opportunity in cancer diagnosis and therapy. Nanopharmaceuticals are drugs containing tiny particles designed to make drugs more effective and less toxic. An important premise of nanomedicine is the enhanced drug accumulation in tumor tissue due to the "leaky" blood vessels seen around the tumors. Until recently, it was believed that leaky blood vessels were not present in blood cancers. This belief resulted in the neglect of the advantages nanotechnology can provide in treating blood cancers. Recent studies, however, have established that leaky blood vessels do play a major role in some blood cancers including MM, providing strong rationale to exploit nanotechnology in managing this disease. Dox and Bort are both Food and Drug Administration-approved therapeutics in MM, albeit with severe toxic side effects prohibiting their use in the broader patient population. The overall objective of this proposed project is to engineer VLA-4 targeted nanoparticles with Dox and Bort payloads with four major benefits: (1) enhanced drug accumulation into tumor, (2) enhanced tumor killing (efficacy), (3) decreased toxic side effects, and (4) overcoming drug resistance. The VLA-4 targeting in our design serves the dual function of selective targeting of MM cells and inhibiting their adhesion to the BM stroma to overcome CAM-DR. The nanoparticular delivery of Dox and Bort increases their efficacy and decreases their toxic side effects. Our preliminary results obtained with VLA-4 targeted Dox-loaded nanoparticles have demonstrated that the engineered nanoparticles significantly enhances drug accumulation in MM tumors, shows increased tumor killing and much reduced toxic-side effects, while at the same time overcoming CAM-DR. In addition, we successfully synthesized Bort-loaded nanoparticles, which showed remarkable cytotoxicity against MM cells. There are no reports of Bort-loaded nanoparticles in the literature, showing the pioneering character of this application. From a technological standpoint, this study establishes a novel strategy to synthesize targeted nanoparticles that overcomes three major hurdles that impede their clinical testing by providing: (i) precisely controlled ratios of drugs and targeting elements per nanoparticle, (ii) a well-defined particle size, and (iii) elimination of batch-to-batch variability in particle synthesis. Resolving these universally observed problems in other targeted nanoparticle synthetic methodologies gives the described system a significant advantage in bench to bedside translational research to clinical trials. My career goals are centered around developing a strong research program to target MM and its bone marrow (BM) microenvironment using multidisciplinary strategies and nanotechnology, with the long-term goal of improving patient outcome. This Career Development Award will greatly aid in my development as a researcher at the forefront of MM and blood cancers, enable me to integrate my work with the key experts in MM, develop further collaborations, help generate m
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510177
Entities
People
- Zihni Bilgicer
Organizations
- United States Army
- University of Notre Dame