Journal
JOURNAL OF CONTROLLED RELEASE
Volume 327, Issue -, Pages 19-25Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2020.08.008
Keywords
Cancer; Tumor microenvironment; Drug delivery systems; Bioconjugation; Albumin
Funding
- CNRS, La Ligue contre le Cancer (Comites Vienne)
- CNRS, La Ligue contre le Cancer (Charente)
- CNRS, La Ligue contre le Cancer (Charente-Maritime)
- CNRS, La Ligue contre le Cancer (Deux-Sevres)
- Sport et Collection
- Region Nouvelle Aquitaine
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The development of selective anticancer drugs avoiding side effects met in the course of almost all current treatments is of major interest for cancer patients. Here, we report on a novel beta-glucuronidase-responsive drug delivery system allowing the in vivo synthesis of triple-loaded albumin conjugate. Following intravenous administration, the glucuronide prodrug reacts in the blood stream with the cysteine-34 residue of circulating albumin through thio-Michael addition, enabling the bioconjugation of three Monomethylauristatin E (MMAE) molecules to the plasmatic protein. The albumin conjugate then accumulates in malignant tissues where tumor-associated beta-glucuronidase triggers the selective release of the whole transported drugs. By operating this way, the trimeric glucuronide prodrug produces remarkable anticancer activity on orthotopic MIA PaCa-2 pancreatic tumors, leading to dramatic reduction or even remission of tumors (3/8 mice).
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