Independent of EPR Effect: A Smart Delivery Nanosystem for Tracking and Treatment of Nonvascularized Intra‐Abdominal Metastases

Abstract Nanoparticle‐based delivery systems (NDS) have impacted the field of cancer therapy on account of the enhanced permeability and retention (EPR) effect that promotes passive accumulation in tumors through the tumor vasculature after intravenous (IV) administration. However, transplanted tumor xenografts on animal models used to justify the feasibility of EPR effect are quite different from clinical tumors in many aspects, a fact that becomes an impediment for NDS to succeed clinical trials. Particularly, early‐stage tumor metastases are usually nonvascularized and incapable of conforming the EPR effect after IV injection. Therefore, it is necessary to develop smart NDS to deliver drugs in an EPR‐independent route. Herein, an NDS‐based treatment approach for intra‐abdominal metastases from ovarian carcinoma is reported. Instead of IV injection, intraperitoneal (IP) injection was employed to directly apply the NDS to the metastatic lesions. The NDS was tailor‐made with targeting groups to actively target the tumor nidus and redox‐responsive drug release to reduce systematic toxicity. Comparing with IV administration, the IP injected NDS could be enriched in metastatic tumor more efficiently, leading to superior therapeutic outcome in vivo. This study provides a successful protocol of EPR‐independent NDS‐based cancer treatment, which may facilitate the clinical translation of nanoparticle‐based cancer therapeutics.