Engineering metalloporphyrin-integrated nanosystems for targeted sono-/ chemo- dynamic therapy of leptomeningeal carcinomatosis through intrathecal administration

Leptomeningeal carcinomatosis (LMC) is a severe complication of cancers that markedly shortens survival and lowers the quality of patients' life, and it still lacks adequate therapeutic programs. Nanomedicine-mediated therapy has recently presented promising to treat malignant tumors, whereas it remains challenging to deliver nanomedicines for high-efficacy LMC treatment owing to the existence of brain-related delivery barriers. Herein, a novel and effective strategy of combined sonodynamic/chemodynamic therapy (SDT/CDT) of LMC by intrathecal injection of a tumor-targeted metalloporphyrin-integrated nanosystem (MOF@MP-RGD) is developed for the first time. Thereinto, intrathecal administration can directly transport such nanosystems into the cerebrospinal fluid (CSF) around the brain and spinal cord to overcome the brain-related barriers for improving delivery. By building of the orthotopic LMC model, the nanosystems are demonstrated to be effectively accumulated in the LMC area post intrathecal administration due to the arginine-glycine-aspartate (RGD) active targeting, and subsequently excreted out of the body by metabolism process. In vivo evaluations reveal the desirable LMC tumor inhibition and survival prolongation of the combined SDT/CDT based on such biocompatible nanosystems, that is superior to the clinically-used chemotherapeutic drug. Therefore, the combination of intrathecal delivery and nanomedicine-mediated therapy holds great potential for clinical LMC treatment.