Abstract

The off-target toxicity of arsenic trioxide chemotherapy is a common Achilles heel of metallodrugs. This limitation is usually mitigated by employing various cargo agents capable of transporting arsenic species to specific sites. More specifically, two of the most explored strategies to address arsenic trioxide's off-target toxicity include: (i) the complexation of As(III) species with chelating agents and (ii) their immobilization, either on the surface or, within non-porous and porous nano-materials. In this work, we have explored the combination of mercaptosuccinic acid, an arsenic chelator, with zirconium oxo-clusters to assemble two new microporous Metal-Organic Frameworks (MOFs), denoted as BCM-1 and BCM-2 (BCM referring to Basque Center for Materials, Applications & Nanostructures). The specific chemical and structural features of these news frameworks have enabled controlling the arsenic loading and release in different scenarios. Specifically, arsenic release accelerates under oxidative conditions due to the rupture of thiol-arsenic bonds, caused by the oxidation of-SH groups to-SO3 within the MOF. Additionally, in acidic conditions typical of cancer microenvironments, the framework itself disassembles, further facilitating arsenic release. The particle size and arsenic loading capacity of BCM-1 can be easily modulated by controlling the synthesis conditions. This strategy has led to the development of micrometric, nanometric and gel-like materials, whose chemical stability in acidic and biological relevant media has been duly assessed. Notably, arsenic release from nano-BCM-1 is able to reverse the growth curve of HeLa cancer cells in approximately 50 h. This discovery paves the way towards the use of metal-chelator organic molecules in assembling new MOF materials capable of controlling the cargo and release of metallodrugs under in-vivo conditions.