Dual ATP and pH responsive ZIF-90 nanosystem with favorable biocompatibility and facile post-modification improves therapeutic outcomes of triple negative breast cancer in vivo

Zeolitic imidazole frameworks (ZIFs) are becoming a notable nanosystem in biomedicine field, due to their unique properties of favorable biocompatibility, pH-responsive degradable structure and high drug loading. Compared with the increasing attention on ZIF-8 in cancer diagnosis and treatment, there is limited research about the bio-application of ZIF-90, especially its in vivo therapeutic efficacy and related toxicity. Here, we synthesize nano ZIF-90 through a fast self-assembling process, and the synthesized nano ZIF-90 is about 75 nm with a negative zeta potential, providing better mitochondria targetability, cell biocompatibility and in vivo survival rate comparing to nano ZIF-8. To further explore the applicability of ZIF-90 in cancer treatment, a facile post-modification is used to conjugate Y₁ receptor ligand [Asn⁶, Pro³⁴]-NPY (AP) on the surface of doxorubicin (DOX)-encapsulated nano ZIF-90. AP-ZIF-90 significantly reduces premature DOX release at physiological pH level, and triggers more effective and faster DOX release inside the tumor cells with dual responsive to high adenosine triphosphate (ATP) and low pH condition. Combining targeted delivery and dual responsive release of DOX significantly improves the therapeutic efficacy of AP-ZIF-90@DOX in MDA-MB-231 tumor bearing mouse, and results in 80% survival rate over 40 days of treatment. At the given dosage, nano ZIF-90 is with excellent biocompatibility in vivo, inducing minimal side effect on the liver and renal functions. Therefore, nano ZIF-90 combines with Y₁ receptor ligand with favorable biocompatibility and dual responsiveness can be used as a promising nanosystem for targeted triple negative breast cancer treatment in vivo.