"Off-on-off"-based metal-organic framework fluorescent sensor for adenosine triphosphate detection and tumor microenvironment-triggered drug release.

Extracellular adenosine triphosphate (ATP) and low extracellular pH are emerging targets for cancer treatment because they are crucial messengers shaping the tumor microenvironment (TME) and regulating tumor progression. Doxorubicin (Dox) is a common chemotherapeutic agent used against numerous solid tumors; however, its use is limited by its adverse effects, such as cardiotoxicity in healthy cells/tissues and multidrug resistance. Thus, using targeted nanocarriers can reduce the side effects of Dox. Herein, we report the construction of an ATP-responsive high fluorescent nanocomposite (ANZIF) that uses gold nanocluster self-assembly embedded in a zeolitic imidazolate framework-8. Based on "off-on-off" fluorescence changes, the ANZIF can be used for sensitive and selective ATP detection, with a detection limit of 4.3 μM. The ANZIF nanoplatform was fabricated using a self-assembly strategy for Dox loading (Dox-ANZIF). This unique nanoplatform exhibited ATP- and low-pH dual-triggered Dox release. In a cytotoxicity study, Dox-ANZIF, triggered by intracellular ATP and low pH, exhibited a selective release of Dox and showed a strong role in cancer cells. Compared with pure Dox, in vivo anticancer efficacy in tumor-bearing mice indicated that Dox-ANZIF significantly improved the antitumor effect and biological safety. This study provides a strategy for constructing a TME-triggered chemotherapy delivery system.