In Situ Autophagy Disruption Generator for Cancer Theranostics

摘要

Cancer remains a serious clinical disease awaiting new effective treatment strategies. Autophagy modulation has emerged as a novel and promising pharmacologic target critical to future drug development and anti-cancer therapy applications. Herein, we constructed an in situ autophagy disruption generator to break the balance of autophagy flow for tumor-targeting therapy. Hollow mesoporous manganese trioxide (Mn2O3) nanoparticles (NPs) were synthesized and conjugated with hyaluronic acid (HA) to form tumor-targeting drug carriers. Then, traditional autophagy inhibitor hydroxychloroquine (HCQ) was loaded into the hollow core of HA-Mn2O3, to form a multifunctional theranostics platform (HA-Mn2O3/HCQ). This nanoplatform displayed specific localization and retention in lysosomes after entering tumor cells. The synchronous release of HCQ and manganese ion (Mn2+) induced lysosomal alkalization and osmotic pressure elevation. Significantly greater lysosomal deacidification and autophagy blockade effect emerged after treatment by this nanoplatform, with in vitro tumor inhibition rate of 92.2%. Imaging experiment proved that it could selectively deliver HCQ to tumor sites and further degrade to realize simultaneous release of Mn2+ and HCQ. Micromorphological and immunofluorescence analysis demonstrated that in situ high concentrations of these two substances would achieve effective autophagy blockade. Pharmacodynamics test showed that this nanogenerator displayed the best therapeutic efficacy with 5.08-fold tumor inhibition ratio compared with the HCQ group. Moreover, the generated Mn2+ can be used as T1 contrast agent for visualizing tumor lesions and monitoring therapeutic effects. Overall, the as-made multifunctional drug-delivery system might provide a promising platform for cancer theranostics upon in situ autophagy disruption.