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Synthesis and Biological Evaluation of Paclitaxel Conjugates Involving Linkers Cleavable by Lysosomal Enzymes and α V β 3 ‐Integrin Ligands for Tumor Targeting
Author(s) -
López Rivas Paula,
Ranđelović Ivan,
Raposo Moreira Dias André,
Pina Arianna,
Arosio Daniela,
Tóvári József,
Mező Gábor,
Dal Corso Alberto,
Pignataro Luca,
Gennari Cesare
Publication year - 2018
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201800447
Subject(s) - conjugate , chemistry , cytotoxicity , stereochemistry , linker , peg ratio , vitronectin , integrin , potency , biotinylation , ligand (biochemistry) , moiety , in vitro , biochemistry , receptor , mathematics , finance , computer science , economics , operating system , mathematical analysis
Two cyclo [DKP‐RGD]‐PTX (PTX = paclitaxel) and two cyclo [RGDfK]‐PTX conjugates containing the Gly‐Phe‐Leu‐Gly (GFLG) linker, which is cleavable by lysosomal enzymes, 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 α v β 3 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 α v β 3 + U87 and in the α v β 3 – 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 α v β 3 + U87/Relative Potency in the α v β 3 – 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 α v β 3 + 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 α v β 3 integrin‐mediated process.