Synthesis and Biological Evaluation of RGD Peptidomimetic–Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers |
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| Authors: | Alberto Dal Corso Dr. Michele Caruso Dr. Laura Belvisi Dr. Daniela Arosio Prof. Dr. Umberto Piarulli Dr. Clara Albanese Dr. Fabio Gasparri Dr. Aurelio Marsiglio Dr. Francesco Sola Dr. Sonia Troiani Dr. Barbara Valsasina Dr. Luca Pignataro Dr. Daniele Donati Prof. Dr. Cesare Gennari |
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| Affiliation: | 1. Università degli Studi di Milano, Dipartimento di Chimica, Via C. Golgi, 19, 20133, Milan (Italy), Fax: (+39)?02‐5031‐4072;2. Nerviano Medical Sciences, Viale Pasteur, 10, 20014, Nerviano (Italy);3. CNR, Istituto di Scienze e Tecnologie Molecolari (ISTM), Via C. Golgi, 19, 20133, Milan (Italy);4. Università degli Studi dell'Insubria, Dipartimento di Scienza e Alta Tecnologia, Via Valleggio, 11, I‐22100, Como (Italy) |
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| 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. |
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| Keywords: | antitumor agents drug delivery integrins peptidomimetics prodrugs |
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