Design and evaluation of micellar nanocarriers for 17-allyamino-17-demethoxygeldanamycin (17-AAG).
17-Allyamino-17-demethoxygeldanamycin (17-AAG) is a potent anticancer agent currently undergoing phases I and II clinical trials. However, the clinical development of 17-AAG has been hindered by its poor aqueous solubility and hepatotoxicity. This study aimed to devise novel micellar nanocarriers for 17-AAG that improve its solubility and retain the incorporated drug for a prolonged period of time. We have found that 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]/D-alpha-tocopheryl polyethylene glycol 1000 (PEG-DSPE/TPGS) mixed micelles (at a 1:2 molar ratio) can deliver 17-AAG at clinically relevant doses. By modulating the concentrations of micelle-forming copolymers, the burst release of 17-AAG from PEG-DSPE/TPGS mixed micelles was substantially reduced with a release half-life up to about 8h. Our (1)H NMR spectroscopy results revealed that the incorporation of TPGS into PEG-DSPE micelles restricted internal molecular motions of copolymers in both the corona and core regions of the micelles, leading to the delayed drug release. Cytotoxicity of 17-AAG formulated in PEG-DSPE/TPGS mixed micelles against human ovarian cancer SKOV-3 cells was comparable to that of free 17-AAG. 17-AAG-loaded PEG-DSPE/TPGS mixed micelles may offer a promising alternative to the current 17-AAG formulations for the treatment of solid tumors.
Chandran
Thripthy
T
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Mercer University, Atlanta, GA 30341, USA.
Katragadda
Usha
U
Teng
Quincy
Q
Tan
Chalet
C
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D016227:Benzoquinones / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D004356:Drug Storage; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D012995:Solubility; D014810:Vitamin E / Q000737:chemistry
D000970:Antineoplastic Agents; D016227:Benzoquinones; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D047029:Lactams, Macrocyclic; D008823:Micelles; D010714:Phosphatidylethanolamines; D014810:Vitamin E; C038089:1,2-distearoylphosphatidylethanolamine; D011092:Polyethylene Glycols; C112765:tanespimycin; C028210:monomethoxypolyethylene glycol; C014225:tocophersolan