Dithiocarbazate-copper complex loaded thermosensitive hydrogel for lung cancer therapy via tumor in situ sustained-release

Abstract

The platinum-based antitumor agents currently available are associated with severe side effects. The solution to these side effects lies in synthesizing non-platinum metal anticancer agents and finding suitable drug delivery strategies. Here we designed and synthesized a series of copper complexes with dithiocarbazate ligands ([Cu^II(L1)Br] 1, [Cu^II(L2)Br] 2, and [Cu^II₂Cu^I(L3)₂(Br)₃] 3), and assessed their anticancer activities. Of the three complexes, complex 3 showed the highest anticancer activity in vitro. The anticancer mechanism of complex 3 involved mitochondrial respiration inhibition and mitochondrial-mediated apoptosis. The efficacy of complex 3 was improved using thermosensitive hydrogels formed from Pluronic F127 to carry the complex for intratumoral drug delivery. The Pluronic F127 hydrogel containing complex 3 (3@F127) exists in the solution form at low temperature and gels rapidly at body temperature. The in vitro release and in vivo gel formation studies showed that the Pluronic F127 hydrogel could prolong the release of complex 3. An in vivo anticancer assessment showed that 3@F127 could delay A549 tumor xenograft growth more effectively with lower systemic toxicity compared to complex 3 alone. This research provides an effective strategy to improve the anticancer ability of copper complexes.