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 β-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 β-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).
Keywords: Albumin; Bioconjugation; Cancer; Drug delivery systems; Tumor microenvironment.
Copyright © 2020 Elsevier B.V. All rights reserved.