Implantable hydrogel embedded dark-gold nanoswitch as a theranostic probe to sense and overcome cancer multidrug resistance.
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.
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139; School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, United Kingdom; and jdconde@mit.edu nartzi@mit.edu.
João
J
Conde
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139;
Nuria
N
Oliva
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 jdconde@mit.edu nartzi@mit.edu.
Natalie
N
Artzi
D000273:Adipose Tissue / Q000187:drug effects / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005453:Fluorescence; D005456:Fluorescent Dyes / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D006046:Gold / Q000737:chemistry*; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D020007:Implants, Experimental; D051379:Mice; D053758:Nanoparticles / Q000627:therapeutic use*; D009369:Neoplasms / Q000175:diagnosis / Q000628:therapy*; D014018:Tissue Distribution / Q000187:drug effects
D005456:Fluorescent Dyes; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D006046:Gold; D005472:Fluorouracil
breast cancer; gold nanobeacons; hydrogels; multidrug resistance; theranostics