Design, synthesis and biological evaluation of novel dimeric and tetrameric cRGD–paclitaxel conjugates for integrin-assisted drug delivery. Issue 27 (15th June 2015)

• Record Type: Journal Article
• Authors: Bianchi, A.; Arosio, D.; Perego, P.; De Cesare, M.; Carenini, N.; Zaffaroni, N.; De Matteo, M.; Manzoni, L.
• Is Part Of: Organic & biomolecular chemistry. Volume 13:Issue 27(2015)
• Page Start: 7530
• Page End: 7541
• Publication Date: 2015-06-15
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/c5ob00497g
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : Novel RGD–PTX multivalent conjugates, presenting enhanced binding for an αv β3 integrin, have been reported. In vivo evaluation of3b showed tumor growth inhibition through administering one-third of the PTX dose. Abstract : Integrins are associated with tumour cell survival and progression, and their expression has been shown to be increased in tumours. Thus, four novel conjugates of the tripeptide integrin ligand Arg-Gly-Asp (RGD) and the cytotoxic agent paclitaxel (cRGD–PTX) were prepared to investigate the potential of the multivalent presentation of the RGD moiety in improving the antitumor efficacy of PTX by tumour targeting. PTX was conjugated to two or four integrin recognizing ligands. The influence of multivalent presentation on in vitro αv β3 -receptor affinity was confirmed. For all the conjugates compared to the previously synthesized monovalent counterparts, an enhancement of the binding strength was observed; this behaviour was more pronounced when considering the tetravalent presented RGD-conjugate. Cell growth inhibition assays on a panel of human tumour cell lines showed remarkable cytotoxic activity for all conjugates with IC50 values in a nanomolar range. Among the four conjugates, the bivalent derivative3b was selected for in vivo studies in an ovarian carcinoma cell model xenografted in immunodeficient mice. A marked antitumor activity was observed, similar to that of PTX, but with a much more favourable toxicity profile. Overall, the novel cRGD–PTX conjugates disclosed here represent promising candidates for further advancement in the domain of targeted anti-tumour therapy.