title: Synthesis and biological evaluation of RGD peptidomimetic-paclitaxel conjugates bearing lysosomally cleavable linkers.
abstract: Two small-molecule-drug conjugates (SMDCs, 6 and 7) featuring lysosomally cleavable linkers (namely the Val-Ala and Phe-Lys peptide sequences) were synthesized by conjugation of the αvβ3-integrin ligand cyclo[DKP-RGD]-CH2NH2 (2) to the anticancer drug paclitaxel (PTX). A third cyclo[DKP-RGD]-PTX conjugate with a nonpeptide "uncleavable" linker (8) was also synthesized to be tested as a negative control. These three SMDCs were able to inhibit biotinylated vitronectin binding to the purified αVβ3-integrin receptor at nanomolar concentrations and showed good stability at pH 7.4 and pH 5.5. Cleavage of the two peptide linkers was observed in the presence of lysosomal enzymes, whereas conjugate 8, which possesses a nonpeptide "uncleavable" linker, remained intact under these conditions. The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing the integrin receptor at different levels: the acute lymphoblastic leukemia cell line CCRF-CEM (αVβ3-) and its subclone CCRF-CEM αVβ3 (αVβ3+). Fairly effective integrin targeting was displayed by the cyclo[DKP-RGD]-Val-Ala-PTX conjugate (6), which was found to differentially inhibit proliferation in antigen-positive CCRF-CEM αVβ3 versus antigen-negative isogenic CCRF-CEM cells. The total lack of activity displayed by the "uncleavable" cyclo[DKP-RGD]-PTX conjugate (8) clearly demonstrates the importance of the peptide linker for achieving the selective release of the cytotoxic payload.
authors.affiliation: Università degli Studi di Milano, Dipartimento di Chimica, Via C. Golgi, 19, 20133, Milan (Italy), Fax: (+39) 02-5031-4072.
authors.forename: Alberto
authors.initials: A
authors.lastname: Dal Corso
authors.forename: Michele
authors.initials: M
authors.lastname: Caruso
authors.forename: Laura
authors.initials: L
authors.lastname: Belvisi
authors.forename: Daniela
authors.initials: D
authors.lastname: Arosio
authors.forename: Umberto
authors.initials: U
authors.lastname: Piarulli
authors.forename: Clara
authors.initials: C
authors.lastname: Albanese
authors.forename: Fabio
authors.initials: F
authors.lastname: Gasparri
authors.forename: Aurelio
authors.initials: A
authors.lastname: Marsiglio
authors.forename: Francesco
authors.initials: F
authors.lastname: Sola
authors.forename: Sonia
authors.initials: S
authors.lastname: Troiani
authors.forename: Barbara
authors.initials: B
authors.lastname: Valsasina
authors.forename: Luca
authors.initials: L
authors.lastname: Pignataro
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Cesare
authors.initials: C
authors.lastname: Gennari
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054659:Diketopiperazines / Q000737:chemistry*; D065546:Drug Liberation; D004355:Drug Stability; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008024:Ligands; D008247:Lysosomes / Q000737:chemistry*; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry*; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D054659:Diketopiperazines; D039302:Integrin alphaVbeta3; D008024:Ligands; D009842:Oligopeptides; D010456:Peptides, Cyclic; D057786:Peptidomimetics; C047981:arginyl-glycyl-aspartic acid; D017239:Paclitaxel
keywords: antitumor agents; drug delivery; integrins; peptidomimetics; prodrugs