In Situ Autophagy Disruption Generator for Cancer Theranostics.

【作者】 Huijuan Zhang, Yanping Ren, Fang Cao, Jianjiao Chen, Chengqun Chen, Junbiao Chang,Lin Hou, Zhenzhong Zhang

【期刊名】 ACS Appl. Mater. Interfaces

【影响因子】 2019年: 8.456

【作者单位】 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China

【年，卷(期)：页码】2019, 11(33): 29641-29654

【关键词】 autophagy blockade, in situ, cancer theranostics, HCQ, 4T1 cells, lysosomal deacidification

【摘要】Cancer remains a serious clinical disease awaiting neweffective treatment strategies. Autophagy modulation has emerged as anovel and promising pharmacologic target critical to future drugdevelopment and anti-cancer therapy applications. Herein, weconstructed an in situ autophagy disruption generator to break thebalance of autophagy flow for tumor-targeting therapy. Hollowmesoporous manganese trioxide (Mn₂O₃) nanoparticles (NPs) weresynthesized and conjugated with hyaluronic acid (HA) to form tumortargeting drug carriers. Then, traditional autophagy inhibitor hydroxychloroquine(HCQ) was loaded into the hollow core of HA-Mn₂O₃, toform a multifunctional theranostics platform (HA-Mn₂O₃/HCQ). Thisnanoplatform displayed specific localization and retention in lysosomes after entering tumor cells. The synchronous release ofHCQ and manganese ion (Mn²⁺) induced lysosomal alkalization and osmotic pressureelevation. Significantly greater lysosomaldeacidification and autophagy blockade effect emerged after treatment by this nanoplatform, with in vitro tumor inhibition rateof 92.2%. Imaging experiment proved that it could selectively deliver HCQ to tumor sites and further degrade to realizesimultaneous release of Mn²⁺ and HCQ. Micromorphological and immunofluorescence analysis demonstrated that in situ highconcentrations of these two substances would achieve effective autophagy blockade. Pharmacodynamics test showed that thisnanogenerator 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 insitu autophagy disruption.

【全文链接】https://pubs.acs.org/doi/10.1021/acsami.9b10578