The reduction of anti-cancer drug antagonism by the spatial protection of drugs with PLA-TPGS nanoparticles.
Docetaxel (DCL) and tamoxifen (TAM) individually are potent drugs in the fight against breast cancer. However when used in combination, they become antagonistic because of differential metabolism of both drugs. We reasoned that by spatially protecting them from metabolizing enzymes with poly (lactide)-D-α-tocopheryl polyethylene glycol succinate (PLA-TPGS) nanoparticles (NPs), we might reduce this drug antagonism. We now report that the drug antagonism between DCL and TAM in MCF7 cell line, was significantly reduced when co-delivered in PLA-TPGS NPs. In addition, this effect of NPs attenuated at high drug concentrations. To investigate the role of NPs in the reduction of drug antagonism, we quantified cellular uptake of the fluorescent model drug coumarin 6 (C6) encapsulated in a rigorous permutation of drugs-nanoparticles ratios. NPs carrying C6 exhibited enhanced cellular uptake over their free C6 counterparts at correspondingly low drug concentrations. This led us to conclude that the reduction of drug antagonism by NPs is correlated to cellular uptake and being in NPs therefore protects both drugs until they are released intracellular for therapeutic anti-cancer effect.
Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore.
Guang-Rong
GR
Tan
Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore.
Si-Shen
SS
Feng
Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore. Electronic address: cheltwd@nus.edu.sg.
David T
DT
Leong
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D003102:Colloids / Q000737:chemistry; D003374:Coumarins / Q000494:pharmacology; D004336:Drug Antagonism; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D011091:Polyesters / Q000138:chemical synthesis / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry; D014810:Vitamin E / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry
D000970:Antineoplastic Agents; D003102:Colloids; D003374:Coumarins; D011091:Polyesters; D014810:Vitamin E; D011092:Polyethylene Glycols; C033616:poly(lactide); C030123:coumarin; C014225:tocophersolan
Anti-cancer drug; Biodegradable polymer; Cancer nanotechnology; Combination therapy; Drug antagonism; Nanomedicine