期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：11
页码：E1278-E1287
DOI：10.1073/pnas.1421229112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe integration of biomaterials science, innovative imaging, and cancer biology now enables the design of smart responsive material platforms for cancer theranostics. We show herein that our developed nanovehicle is able to sense and silence a multidrug resistance gene based on its expression in the tumor microenvironment, followed by local chemotherapeutic drug release, with a significant tumor regression not achieved otherwise. This ON/OFF molecular nanoswitch approach can be used to reverse the resistance to many other chemotherapeutic drugs and can serve as a universal gene therapy and drug delivery vehicle for cancer therapy. This disease-responsive platform can revolutionize clinical outcome and cancer patients' point of care. Multidrug resistance (MDR) in cancer cells is a substantial limitation to the success of chemotherapy. Here, we describe facile means to overcome resistance by silencing the multidrug resistance protein 1 (MRP1), before chemotherapeutic drug delivery in vivo with a single local application. Our platform contains hydrogel embedded with dark-gold nanoparticles modified with 5-fluorouracil (5-FU)-intercalated nanobeacons that serve as an ON/OFF molecular nanoswitch triggered by the increased MRP1 expression within the tumor tissue microenvironment. This nanoswitch can sense and overcome MDR prior to local drug release. The nanobeacons comprise a 5-FU intercalated DNA hairpin, which is labeled with a near-infrared (NIR) dye and a dark-quencher. The nanobeacons are designed to open and release the intercalated drug only upon hybridization of the DNA hairpin to a complementary target, an event that restores fluorescence emission due to nanobeacons conformational reorganization. Despite the cross-resistance to 5-FU, more than 90% tumor reduction is achieved in vivo in a triple-negative breast cancer model following 80% MRP1 silencing compared with the continuous tumor growth following only drug or nanobeacon administration. Our approach can be applied to reverse cross-resistance to other chemotherapeutic drugs and restore treatment efficacy. As a universal nanotheranostic probe, this platform can pave the way to early cancer detection and treatment.
关键词：hydrogels ; gold nanobeacons ; theranostics ; breast cancer ; multidrug resistance
