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Targeted drug delivery to cancer cells. Since most conventional chemotherapy does not target cancer cells specifically, and is toxic to normal cells, a method must be developed to selectively deliver the anticancer drugs. This task is however difficult, owing to many factors, among those, the similarity between the cancerous and normal cells, the need for site-specific systemic drug administration, and sensitivity of the molecules to enzymatic degradations. We develop (together with Dr. Ayelet David; Pharmacology Dept. BGU), a model system with improved efficacy of anticancer drugs, by employing water soluble copolymers that selectively target the tumor vascular endothelial cells. These conjugates were equipped with anticancer drug molecules, Doxorubicin, and specific peptide-based ligands that can selectively bind with high affinity to E-selectin, which is a molecular marker expressed exclusively by vascular endothelial cells during inflammation and cancer. We have shown that such constructs target tumor vasculature via the E-selectin-mediated interactions, and that this increases the cytotoxicity against vascular endothelial cells. In recent studies, we have further found in vivo, that systemic administration of these copolymers in Lewis lung carcinoma bearing mice model, significantly prolonged the mice survival and dramatically reduced tumor growth. Recently, we have developed radically different approach for specific delivery of these drug-bearing copolymers, which makes use of passive delivery of macromolecules equipped with ‘caged’ cell penetrating peptides. Shining light on conjugates at the vicinity of the cancer cells resulted in release of the cages and rapid cell penetration.

 

References:

  1. Y. Shamay, L. Shpirt, G. Ashkenasy, A. David  “​Complexation of Cell-Penetrating Peptide-Polymer Conjugates with Polyanions Controls Cells Uptake of HPMA Copolymers and Anti-tumor Activity ” Pharm. Res. 2013, DOI 10.1007/s11095-013-1198-x.

  2. Y. Shamay, L. Adar, G. Ashkenasy, A. David  “Light Induced Drug Delivery to Cancer Cells”   Biomaterials 2011, 32, 1377-1386.

  3. Y. Shamay, D. Paulin, G. Ashkenasy, A. David “​E-selectin binding peptide-Polymer-Drug Conjugates and their Selective Cytotoxicity against Vascular Endothelial Cells” Biomaterials 2009, 30, 6460-6468.

  4. Y. Shamay, D. Paulin, G. Ashkenasy, A. David  “​Multivalent Display of Quinic Acid Ligands for Targeting E-selectin Expressing Cells” J. Med. Chem. 2009, 52, 5906-5915.