Neutrophil Elastase Promotes Linker Cleavage and Paclitaxel Release from an Integrin‐Targeted Conjugate

This work takes advantage of one of the hallmarks of cancer, that is, the presence of tumor infiltrating cells of the immune system and leukocyte‐secreted enzymes, to promote the activation of an anticancer drug at the tumor site. The peptidomimetic integrin ligand cyclo(DKP‐RGD) was found to accumu...

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Bibliographic Details
Published in:Chemistry : a European journal 2019-02, Vol.25 (7), p.1696-1700
Main Authors: Raposo Moreira Dias, André, Pina, Arianna, Dean, Amelia, Lerchen, Hans‐Georg, Caruso, Michele, Gasparri, Fabio, Fraietta, Ivan, Troiani, Sonia, Arosio, Daniela, Belvisi, Laura, Pignataro, Luca, Dal Corso, Alberto, Gennari, Cesare
Format: Article
Language:English
Subjects:
Antineoplastic Agents, Phytogenic - chemistry
Antineoplastic Agents, Phytogenic - metabolism
Antineoplastic Agents, Phytogenic - pharmacology
antitumor agents
Cancer
Cell activation
Cell Line, Tumor
Cell Proliferation - drug effects
Chemistry
Cleavage
Communication
Communications
Conjugates
drug delivery
Drug Liberation
Elastase
Humans
Immune system
inflammation
Integrin alphaVbeta3 - genetics
Integrin alphaVbeta3 - metabolism
Kidney cancer
Leukocyte Elastase - metabolism
Leukocytes
Ligands
Microscopy, Confocal
Neutrophils
Oligopeptides - chemistry
Paclitaxel
Paclitaxel - chemistry
Paclitaxel - metabolism
Paclitaxel - pharmacology
Renal cell carcinoma
Substrates
Therapeutic applications
Tumors
Vitronectin - chemistry
Vitronectin - metabolism
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Summary:This work takes advantage of one of the hallmarks of cancer, that is, the presence of tumor infiltrating cells of the immune system and leukocyte‐secreted enzymes, to promote the activation of an anticancer drug at the tumor site. The peptidomimetic integrin ligand cyclo(DKP‐RGD) was found to accumulate on the surface of αvβ3 integrin‐expressing human renal cell carcinoma 786‐O cells. The ligand was conjugated to the anticancer drug paclitaxel through a Asn‐Pro‐Val (NPV) tripeptide linker, which is a substrate of neutrophil‐secreted elastase. In vitro linker cleavage assays and cell antiproliferative experiments demonstrate the efficacy of this tumor‐targeting conjugate, opening the way to potential therapeutic applications. Exploiting inflammation in cancer: A RGD‐drug conjugate accumulates on the surface of integrin‐expressing human renal cell carcinoma cells and releases paclitaxel upon linker cleavage mediated by neutrophil‐secreted elastase.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201805447