Associate Professor
Ph.D. 2002
cancer, nano medicine, polymers, pharmacology |
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- Ph.D.: The Hebrew University of Jerusalem
- Post-doctorate: Weizmann Institute of Science
- Nano-sized Polymeric Carriers for Cancer Diagnostics and Therapy
- Our laboratory focuses on the design of novel drug delivery systems to target drugs and diagnostic agents selectively to diseased sites in the body. Targeted drug delivery systems have the potential to offer more effective treatment with significantly reduced adverse effects through specific interactions with the intended cells.
- the design of novel biomedical polymers to target drugs and diagnostic agents selectively to cancerous and inflamed tissues;
- synthesis of stimuli-sensitive biomedical polymers to improve drug penetration into cancerous tissues;
- generation of self-assembled block-copolymers for oligonucleotides (DNA, miRNA, siRNA) delivery.
- Drugs administered to treat cancers typically distribute randomly throughout the body, resulting in a lower concentration of the drug at the tumor and some severe side effects due to the lack of specificity of the anticancer agent. Targeted drug delivery systems have the potential to offer more effective treatment with significantly reduced adverse effects through specific interactions with the intended cells. Over the last few years we have designed and synthesized various nano-sized polymeric carriers that can target both the tumor and its microenvironment (1-6). These nanocarriers can passively accumulate in solid tumors following intravenous administration by slow leakage across highly permeable neovasculature, owing to the enhanced permeability and retention (EPR) effect. Our water-soluble polymeric carriers, including polymer-drug conjugates and self-assembeled polymeric micelles, can be further equipped with targeting ligands (short peptide and oligosaccharide) specific for endothelial and cancer cells markers, to improve the efficacy of anticancer drugs and oligonucleotides and diminish non-specific toxicity in the treatment of cancer. For example, active targeting of our polymer-drug (Doxorubicin, DOX) conjugates to E-selectin, overexpressed by angiogenic endothelial cells, was found very effective in improving the cytotoxicity of the targeted copolymer (P-Esbp-DOX) towards human immortalized vascular endothelial cells (IVECs) that over-express E-selectin, as compared to treatment with the non-targeted P-DOX conjugate and DOX alone (2). This study is currently being pursued to reveal the in vivo toxicity in tumor-bearing mice.
- We further developed novel polymeric scaffolds to increase the drug concentration in selected sites by the use of caged cell penetrating peptide (cCPP) sequences that could trigger penetration into specific type of cells only once illuminated by light, and thus can overcome the major drawback for the CPP clinical development, i.e. the lack of cell specificity (7). We demonstrated that the neutralization of the cationic resudues of the CPP with photo-cleavable caging molecules can lead to conditional light-dependent cell penetration functionality. The cell viability profiles revealed a “light switch” in cytotoxicity of polymer conjugate bearing a proapoptotic drug D-(KLAKLAK)2 and cCPP (P-(cCPP)-KLAK).
- Polymeric Nanomedicines, Targeted Drug Delivery, Macromolecular therapeutic, Self-assembly of polymeric drug carriers
Major expertise and techniques in the lab
- • Synthesis and characterization of biocompatible polymer conjugates • Biological evaluation of drug delivery systems for anticancer and anti-inflammatory activities, as protein delivery systems, and new biomaterials. Major equipment in the lab: AKTA-FPLC system (Pharmacia) equipped with UV and refractive index (RI) detectors, a complete HPLC system (Waters 2695 Alliance) equipped with Diode Array detector, Flow Cytometry System (GUAVA EasyCyte), Infinite M-200 Microplate Reader (Tecan)
Publications and funding summary / representative publications and grants
- David A., Kopeckova P., Rubinstein A. and Kopecek J., Design of Multivalent Glycoside Ligand for Selective Targeting of HPMA Copolymer-Doxorubicin Conjugates to Human Colon Cancer Cells, Eur. J. Cancer, 40: 148-57, 2004
- Shamay, Y., Paulin, D., Ashkenasy, G., David, A. Multivalent Display of Quinic Acid Based Ligands for Targeting E-Selectin Expressing Cells. J Med Chem , 52, 5906-15, 2009.
- Shamay, Y., Paulin, D., Ashkenasy, G., David, A. E-selectin Binding Peptide-Polymer-Drug Conjugates and Their selective Cytotoxicity Against Vascular Endothelial Cells. Biomaterials , 30, 6460-8, 2009.
- Adar, L., Shamay, Y., Journo, G., David, A. Pro-apoptotic Peptide-Polymer Conjugates to Induce Mitochondrial-Dependent Cell Death. Polymers for Advanced Technologies, 22, 199-208, 2011.
- Kopansky, E. Shamay, Y., David, A. Peptide-directed HPMA copolymer-DOX conjugates as targeted therapeutics for colorectal cancer. J Drug Target 19, 933-943, 2011.
- Journo-Gershfeld, G. Israeli-Kapp, D. Shamay, Y. Kopecek, J., David, A. "Hyaluronan Oligomers-HPMA Copolymer Conjugates for Targeting Paclitaxel to CD44-overexpressing Ovarian Carcinoma. Pharm. Res. 29(4): 1121-33, 2012.
- Shamay, Y., Adar, L., Ashkenasy, G., David, A. Light Induced Drug Delivery into Cancer Cells, Biomaterials , 32, 1377-86, 2011.
- Funding Summary :
- ISF, BSF, Office of the Israeli Chief Scientist (OCS)
- • Prof. Ron N. Apte, Ben-Gurion University • Prof. Jindrich Kopecek, University of Utah
Suggested multi-disciplinary research project / research focus topics
- Nanomedicines for Personalized Therapeutics and diagnostics