Complete breakdown of copper-free clickable doxorubicin nanoclusters for real-time tumor proliferation tracking

Abstract

Size-dependent localization of nanoscale carriers is essential for enhancing therapeutic windows and minimizing side effects in anticancer therapy. Therefore, we prepared polymeric nanoparticle (NP) clusters that could be clicked in response to the surrounding enzyme levels in tumor tissues to accomplish diagnostic and therapeutic systems with a single nanocluster. Multiarmed poly(ethylene glycol) (PEG) was conjugated with multiple molecules of doxorubicin (DOX), and the longest arm was designed to be abolished in response to matrix metalloproteinase (MMP) levels. These PEG conjugates self-assembled into anticancer NPs, and PEG shells were peeled at high threshold MMP levels. These DOX NPs were copper-free clicked with azide-functionalized quantum dots in response to the surrounding MMP levels. Therefore, the fluorescence of the systems was quenched, which was dependent on the tumor cell types. Ex vivo experiments on harvested tumor tissues validated the correlation between fluorescence quenching and tumor weight, highlighting the potential of these NPs as tools for monitoring tumor progression and therapeutic efficacy.