Synthesis and biological evaluation of RGD peptidomimetic-paclitaxel conjugates bearing lysosomally cleavable linkers

Chemistry : a European Journal
A Dal CorsoC Gennari

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 antige...Continue Reading

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Citations

Dec 22, 2015·Advanced Drug Delivery Reviews·Daniela Arosio, Cesare Casagrande
Apr 11, 2017·Future Medicinal Chemistry·Sotirios KatsamakasVasiliki Sarli
Apr 28, 2017·Chemistry : a European Journal·Simone ZanellaCesare Gennari
Feb 1, 2017·Chembiochem : a European Journal of Chemical Biology·Nerea Zabala-UncillaClaudio Palomo
Jul 1, 2017·Journal of Peptide Science : an Official Publication of the European Peptide Society·Christine WeissNorbert Sewald
Jul 26, 2018·Future Medicinal Chemistry·Theodora ChatzisideriVasiliki Sarli
Nov 20, 2018·Chemistry : a European Journal·André Raposo Moreira DiasCesare Gennari
Aug 15, 2019·Drug Development Research·Hang HuDefeng Xu
Apr 1, 2020·Chemistry : a European Journal·Arianna PinaDidier Boturyn
Aug 18, 2017·Chemistry : a European Journal·André Raposo Moreira DiasCesare Gennari
Mar 10, 2018·Beilstein Journal of Organic Chemistry·Lizeth BoderoUmberto Piarulli
Apr 14, 2017·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Bowen LiShuizhu Wu
Apr 26, 2019·Organic & Biomolecular Chemistry·Paula López RivasCesare Gennari
Dec 20, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Silvia PanzeriUmberto Piarulli
Feb 7, 2018·Journal of Controlled Release : Official Journal of the Controlled Release Society·Yanqin LiangQiang Zhang
Nov 29, 2016·Journal of Controlled Release : Official Journal of the Controlled Release Society·Samuele CazzamalliDario Neri
Jan 19, 2021·ACS Biomaterials Science & Engineering·Jyothi B NairKaustabh Kumar Maiti

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