Intrinsic nucleus-targeted ultra-small metal–organic framework for the type I sonodynamic treatment of orthotopic pancreatic carcinoma

Background: Sonodynamic therapy (SDT) strategies exhibit a high tissue penetration depth and can achieve therapeutic efficacy by facilitating the intertumoral release of reactive oxygen species (ROS) with a short lifespan and limited diffusion capabilities. The majority of SDT systems developed to date are of the highly O₂-dependent type II variety, limiting their therapeutic utility in pancreatic cancer and other hypoxic solid tumor types. Results: Herein, a nucleus-targeted ultra-small Ti-tetrakis(4-carboxyphenyl)porphyrin (TCPP) metal–organic framework (MOF) platform was synthesized and shown to be an effective mediator of SDT. This MOF was capable of generating large quantities of ROS in an oxygen-independent manner in response to low-intensity ultrasound (US) irradiation (0.5 W cm⁻²), thereby facilitating both type I and type II SDT. This approach thus holds great promise for the treatment of highly hypoxic orthotopic pancreatic carcinoma solid tumors. This Ti-TCPP MOF was able to induce in vitro cellular apoptosis by directly destroying DNA and inducing S phase cell cycle arrest following US irradiation. The prolonged circulation, high intratumoral accumulation, and nucleus-targeting attributes of these MOF preparations significantly also served to significantly inhibit orthotopic pancreatic tumor growth and prolong the survival of tumor-bearing mice following Ti-TCPP + US treatment. Moreover, this Ti-TCPP MOF was almost completely cleared from mice within 7 days of treatment, and no apparent treatment-associated toxicity was observed. Conclusion: The nucleus-targeted ultra-small Ti-TCPP MOF developed herein represents an effective approach to the enhanced SDT treatment of tumors in response to low-intensity US irradiation. Graphic abstract: [Figure not available: see fulltext.]