REAL

Synthesis and Biological Evaluation of Paclitaxel Conjugates Involving Lysosomally Cleavable Linkers and αVβ3-Integrin Ligands for Tumor Targeting

Rivas, Paula López and Ranđelović, Ivan and Dias, André Raposo Moreira and Pina, Arianna and Arosio, Daniela and Tóvári, József and Mező, Gábor and Dal Corso, Alberto and Pignatoro, Luca and Genarri, Cesare (2018) Synthesis and Biological Evaluation of Paclitaxel Conjugates Involving Lysosomally Cleavable Linkers and αVβ3-Integrin Ligands for Tumor Targeting. EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2018 (23). pp. 2902-2909. ISSN 1434-193X

[img]
Preview
Text
Rivas_EurOC_2018.pdf - Accepted Version

Download (984kB) | Preview

Abstract

Two cyclo[DKP-RGD]-PTX (PTX = paclitaxel) and two cyclo[RGDfK]-PTX conjugates containing the lysosomally cleavable Gly-Phe-Leu-Gly (GFLG) linker were synthesized and compared to two cyclo[DKP-RGD]-Val-Ala-PTX conjugates. The conjugates were evaluated for their ability to inhibit biotinylated vitronectin binding to the isolated αvβ3 receptor, retaining good binding affinity, in the same nanomolar range of the free ligands. Cell viability assays were performed for the six conjugates in the αvβ3+ U87 and in the αvβ3– HT29 cell lines. Loss of potency was observed for all the conjugates, attenuated by the presence of a tetraethylene glycol (PEG-4) spacer. A good Targeting Index (TI = Relative Potency in the αvβ3+ U87 / Relative Potency in the αvβ3– HT29) was displayed by the conjugates, in particular by cyclo[DKP-RGD]-PEG-4-Val-Ala-PTX 9 (TI = 533). This conjugate was tested in the αvβ3+ U87 cell line in the presence of 50-fold excess free cyclo[DKP-RGD] ligand 2. In this competition experiment, a fivefold decrease of the conjugate cytotoxicity was calculated, suggesting that the conjugate is possibly internalized by an αvβ3 integrin-mediated process.

Item Type: Article
Subjects: Q Science / természettudomány > QD Chemistry / kémia > QD04 Organic chemistry / szerves kémia
R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia
Depositing User: Dr Katalin Uray
Date Deposited: 31 Jan 2019 09:39
Last Modified: 22 Jun 2019 23:15
URI: http://real.mtak.hu/id/eprint/90838

Actions (login required)

Edit Item Edit Item