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Volume 8, Issue 6 (Suppl) J Bioequiv Availab
ISSN: 0975-0851 JBB, an open access journal
Page 42
Notes:
Biopharma 2016
September 14-16, 2016
conferenceseries.com
September 14-16, 2016 San Antonio, USA
2nd International Conference & Expo on
Biopharmaceutics and Biologic Drugs
Novel tri-functional lipid nanoparticles for immunotherapy of resistant HER2-positive breast
Sihem Bihorel
University of Florida, USA
Purpose: Breast cancer (BC) is the second leading cause of cancer deaths in women, and about 25% of BCs have overexpression
of the HER2 receptor. Although HER2 targeted therapies have shown considerable improvement in HER2-positive BC patients’
outcome, treatment resistance remains a clinical challenge. Here, we sought to develop and evaluate a novel tri-functional lipid nano-
particulate (TFLP) drug delivery system that overcomes HER2 treatment resistance by dually targeting HER2 on BC cells and CD3
receptors on cytotoxic T-lymphocytes (CTLs).
Material & Methods: Anti-HER2 (Trastuzumab) and anti-CD3 (OKT-3) antibodies were conjugated to lipid nanoparticles by
the micelle-transfer method, and the resulting formulation was purified by dextran gradient ultra-centrifugation. Targeted lipid
nanoparticles were formulated with a fluorescent lipophilic dye, DiD, for studying receptor binding and internalization. Studies
were conducted with HER2-positive BT474 cells and CD3-positive Jurkat cells using flow cytometry analyses. Doxorubicin HCl
(DXR) was encapsulated in the nanoparticles by the remote-loading technique for cell-kill experiments. In vitro cell-kill studies were
conducted by co-culturing BT474 as the target cells, and peripheral blood mononuclear cells as the effector cells, at varying ratios.
Results: Purified formulations were successfully characterized for conjugation by determining protein to lipid ratio. Flow cytometry
analyses demonstrated successful cell binding and/or internalization of the TFLP with both the HER2 and CD3-positive cell lines.
Moreover, these dual-targeted nanoparticles were able to retarget T cells to kill HER2 positive BC cells, and showed improved efficacy
compared to non-targeted and plain HER2-targeted formulations in vitro .
Conclusion: A novel TFLP drug delivery system that targets HER2 receptors on tumor cells, CD3 on CTLs, and is able to slowly
release DXR was successfully developed and evaluated in vitro on HER2 overexpressing BC cells. Our findings showed great promise
at overcoming resistance to present HER2 targeted BC therapies, and may translate into improved anti-tumor activity clinically
compared to other treatment options.
Biography
Sihem Bihorel (Ait-Oudhia) utilizes quantitative systems pharmacology approaches to guide the development of new therapies and the identification of promising
combination therapies as well as of novel biomarkers in Oncology. She integrates quantitative systems pharmacology with PK/PD modeling and simulation to
advance drug discovery and development, and leverage the understanding of drugs action which holds great promise to facilitate translational research. Her
research is also focused on investigating how priming solid tumors with a pro-apoptotic agent then combining a subsequent large protein therapeutic and an
antiagiogenic agent can defeat drug resistance and treatment failure in cancer and further enhance the efficacy of targeted anticancer agents, and translating these
findings toward clinical settings. Prior to this position, she held the position of Research Assistant Professor at the State University of New York at Buffalo where
she was also trained as a Post-doc and received her PhD from the same.
Sihem Bihorel, J Bioequiv Availab 2016, 8:6 (Suppl)