(676e) Autophagy Targeting Nano-Prodrugs for Synergistic Therapy of Metastatic Cancer

Cancer metastasis accounts for over 90% of the carcinoma-related mortality. During metastatic dissemination, metastatic tumor cells may suffer from anoikis, a form of programmed cell death happened in extracellular matrix (ECM)-detached cells. However, autophagy induction can prevent tumor cells from anoikis by multiple mechanisms. In addition, disassembly of focal adhesions by autophagic degradation contributes to the metastatic progression. Here, we constructed redox-responsive dual-polymeric-prodrug nanoparticles delivering SN38 (active metabolite of irinotecan) and hydroxychloroquine (HCQ, an FDA approved autophagy inhibitor) with optimal synergetic ratio. The combo nanoparticles (Combo NPs) containing PEG-PSN38 and PEG-PHCQ at 1:5 molar ratio displayed synchronized release in the reductive tumor environment, and remarkably improved the pharmacokinetic behaviors and tumor accumulations of both SN38 and HCQ. Importantly, the Combo NPs displayed efficient inhibition of tumor growth and metastasis using 4T1-bearing orthotopic and lung metastatic breast cancer models. Mechanism studies indicated that autophagy inhibition by the Combo NPs could attenuate the migration and invasion of 4T1 cells through impairing anoikis resistance and degradation of paxillin (a key component of focal adhesions). Therefore, the reported polymeric nano-prodrugs rationally combined autophagy inhibition and chemotherapy, representing a potential therapeutic approach for blocking metastatic dissemination of breast cancer.