Synthesis,biological studies and molecular dynamics of new anticancer RGD-based peptide conjugates for targeted drug delivery |
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| Institution: | 1. Department of Biological Chemistry, Ariel University, Ariel 40700, Israel;2. The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel;3. Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel;4. Department of Chemical Engineering, Ariel University, Ariel 40700, Israel;1. Dept. Chemical Engineering, Ariel University, Ariel, 40700, Israel;2. Dept. Chemical Sciences, Ariel University, Ariel, 40700, Israel;1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China;2. Department of Chemistry, Renmin University of China, Beijing 100872, PR China;1. Department of Chemistry, Aristotle University of Thessaloniki, University Campus, 54124, Thessaloniki, Greece;2. Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, University Campus, 54124, Thessaloniki, Greece;3. Laboratory of Pharmacology, Medical School National and Kapodistrian University of Athens 75 Mikras Asias Street, Athens, 11527, Greece;4. Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NTNU, N-7491 Trondheim, Norway;5. Department of Physics, Norwegian University of Science and Technology, NTNU, N-7491 Trondheim, Norway |
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| Abstract: | New cyclic RGD peptide-anticancer agent conjugates, with different chemical functionalities attached to the parent peptide were synthesized in order to evaluate their biological activities and to provide a comparative study of their drug release profiles. The Integrin binding c(RGDfK) penta-peptide was used for the synthesis of Camptothecin (CPT) carbamate and Chlorambucil (CLB) amide conjugates. Substitution of the amino acid Lys with Ser resulted in a modified c(RGDfS) with a new attachment site, which enabled the synthesis of an ester CLB conjugate. Functional versatility of the conjugates was reflected in the variability of their drug release profiles, while the conserved RGD sequence of a selective binding to the αv integrin family, likely preserved their recognition by the Integrin and consequently their favorable toxicity towards targeted cancer cells. This hypothesis was supported by a computational analysis suggesting that all conjugates occupy conformational spaces similar to that of the Integrin bound bio-active parent peptide. |
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| Keywords: | RGD Conjugate Targeted drug delivery Chemo-stability Bio-stability Cancer Drug release profiles Molecular dynamics |
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