title: A 3-in-1 polymeric micelle nanocontainer for poorly water-soluble drugs.
abstract: Poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b-PLA) micelles have a proven capacity for drug solubilization and have entered phase III clinical trials as a substitute for Cremophor EL in the delivery of paclitaxel in cancer therapy. PEG-b-PLA is less toxic than Cremophor EL, enabling a doubling of paclitaxel dose in clinical trials. We show that PEG-b-PLA micelles act as a 3-in-1 nanocontainer for paclitaxel, 17-allylamino-17-demethoxygeldanamycin (17-AAG), and rapamycin for multiple drug solubilization. 3-in-1 PEG-b-PLA micelles were ca. 40 nm in diameter; dissolved paclitaxel, 17-AAG, and rapamycin in water at 9.0 mg/mL; and were stable for 24 h at 25 °C. The half-life for in vitro drug release (t(1/2)) for 3-in-1 PEG-b-PLA micelles was 1-15 h under sink conditions and increased in the order of 17-AAG, paclitaxel, and rapamycin. The t(1/2) values correlated with log P(o/w) values, implicating a diffusion-controlled mechanism for drug release. The IC(50) value of 3-in-1 PEG-b-PLA micelles for MCF-7 and 4T1 breast cancer cell lines was 114 ± 10 and 25 ± 1 nM, respectively; combination index (CI) analysis showed that 3-in-1 PEG-b-PLA micelles exert strong synergy in MCF-7 and 4T1 breast cancer cell lines. Notably, concurrent intravenous (iv) injection of paclitaxel, 17-AAG, and rapamycin using 3-in-1 PEG-b-PLA micelles was well-tolerated by FVB albino mice. Collectively, these results suggest that PEG-b-PLA micelles carrying paclitaxel, 17-AAG, and rapamycin will provide a simple yet safe and efficacious 3-in-1 nanomedicine for cancer therapy.
authors.affiliation: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin 53705-2222, USA.
authors.forename: Ho-Chul
authors.initials: HC
authors.lastname: Shin
authors.forename: Adam W G
authors.initials: AW
authors.lastname: Alani
authors.forename: Hyunah
authors.initials: H
authors.lastname: Cho
authors.forename: Younsoo
authors.initials: Y
authors.lastname: Bae
authors.forename: Jill M
authors.initials: JM
authors.lastname: Kolesar
authors.forename: Glen S
authors.initials: GS
authors.lastname: Kwon
mesh_terms: D016227:Benzoquinones / Q000737:chemistry; D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry; D019344:Lactic Acid / Q000737:chemistry; D008823:Micelles; D008962:Models, Theoretical; D017239:Paclitaxel / Q000737:chemistry; D011091:Polyesters; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D020123:Sirolimus / Q000737:chemistry; D012995:Solubility; D058570:TOR Serine-Threonine Kinases / Q000737:chemistry; D014867:Water / Q000737:chemistry*
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008823:Micelles; D011091:Polyesters; D011108:Polymers; D014867:Water; D019344:Lactic Acid; D011092:Polyethylene Glycols; C033616:poly(lactide); C112765:tanespimycin; D058570:TOR Serine-Threonine Kinases; D017239:Paclitaxel; D020123:Sirolimus