title: Synthesis, biological studies and molecular dynamics of new anticancer RGD-based peptide conjugates for targeted drug delivery.
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.
authors.affiliation: Department of Biological Chemistry, Ariel University, Ariel 40700, Israel; The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Gilad
authors.affiliation: Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Noy
authors.affiliation: Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Senderowitz
authors.affiliation: The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Albeck
authors.affiliation: Department of Chemical Engineering, Ariel University, Ariel 40700, Israel.
authors.forename: M A
authors.initials: MA
authors.lastname: Firer
authors.affiliation: Department of Biological Chemistry, Ariel University, Ariel 40700, Israel. Electronic address: garyg@ariel.ac.il.
authors.forename: G
authors.initials: G
authors.lastname: Gellerman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002166:Camptothecin / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002699:Chlorambucil / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002219:Carbamates; D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide; D002699:Chlorambucil; D002166:Camptothecin
keywords: Bio-stability; Cancer; Chemo-stability; Conjugate; Drug release profiles; Molecular dynamics; RGD; Targeted drug delivery