Synthesis and biological evaluations of a monomethylauristatin E glucuronide prodrug for selective cancer chemotherapy

In situ targeted activation of an anticancer agent using ultrasound-triggered release of composite droplets

“…A glucuronide prodrug of monomethylauristatin E (MMAE-glu) [25][26][27][28][29][30][31][32] was chosen to perform this study [33,34]. Indeed, MMAE is a potent antimitotic agent currently employed in human for the treatment of lymphomas under the form of the brentuximab vedotin, an antibody-drug conjugate that reached the market in 2011 [35].…”

“…Moreover, since the β-glucuronidase is over-expressed in the microenvironment of almost all solid tumors [26,36,37], ultrasound-triggered release of the prodrug in the vicinity of the tumor mass should be followed by the local enzyme-mediated release of the active drug via the self-immolative mechanism illustrated in Figure 1 [38,39]. This strategy has proved its efficacy in numerous animal models over the years [29,37,[40][41][42][43][44][45], as for example showed by Papot and co-workers in mice [30]. These prodrugs are rapidly eliminated by the kidneys, thus lowering their concentration in tumors.…”

“…A suspension of droplets at 0.01% v/v was used in the course of this study. Regarding the in situ activation of MMAE-glu by the β-glucuronidase (β-glu), Legigan et al [30] showed that complete conversion of the prodrug intro MMAE in the presence of β-glucuronidase was almost completely Fig. 3.…”

Monitoring glycosidase activity for clustered sugar substrates, a study on β-glucuronidase

“…23 The elevated GUS activity in specic tumours has also been successfully exploited for the selective delivery of cytotoxic agents. 24 Potent anticancer drugs such as doxorubicin, 25,26 or monomethylauristatine E, 27 have been successfully targeted to various tumours by the means of b-glucuronidase-responsive drug delivery systems, leading to impressive therapeutic efficacy in mice. Inhibition of GUS microbiota may also be required to alleviate drug and endobiotic toxicity.…”

Development of an embedded multimodality imaging platform for onco-pharmacology using a smart anticancer prodrug as an example

“…The experimental design for this work was to implement a multimodal imaging approach for applications to onco-pharmacology. As an example, a novel prodrug (a β-Glucuronidase-Responsive Albumin-Binding Prodrug of MMAE) was studied in several experimental cancer models 21,22 . The embedded multimodal imaging platform was used to investigate therapeutic effects on both superficial and orthotopic tumor models, in order to provide essential information on a wide range of specific tumor growth parameters.…”