title: Epothilone B-based 3-in-1 polymeric micelle for anticancer drug therapy.
abstract: Epothilones are microtubule inhibitors that are promising alternatives to paclitaxel due to enhanced anticancer efficacy. While epothilones are slightly more water soluble than paclitaxel and more active against paclitaxel-resistant cells, they still require formulation with Cremophor EL and/or cosolvents and drug resistance still limits therapeutic efficacy. In this report, we showed that the combinational treatment of epothilone B (EpoB), 17-N-allylamino-17-demethoxygeldanamycin (17-AAG, Hsp90 inhibitor), and rapamycin (mTOR inhibitor) displays strong anticancer activity in vitro and in vivo. To address the poor water solubility of this 3 drug-combination, they were co-loaded into poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-b-PLA) micelles, and the 3-in-1 loaded PEG-b-PLA micelle (m-EAR) was characterized in terms of drug loading efficiency, particle size, release kinetics. The m-EAR achieved high levels of all three drugs in water; formed micelles with hydrodynamic diameters at ca. 30nm and released the drugs in a sustained manner in vitro at rates slower than individually loaded PEG-b-PLA micelles. In A549-derived xenograft mice, m-EAR (2.0, 15.0, and 7.5mg/kg) caused tumor regression after four weekly injections, whereas EpoB alone (2.0mg/kg) was the same as control. No severe changes in body weight relative to PBS control were observed, attesting to the safety of m-EAR. Collectively, these results suggest that m-EAR provides a simple, but effective and safe EpoB-based combination nanomedicine for cancer therapy.
authors.affiliation: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, United States.
authors.forename: Dae Hwan
authors.initials: DH
authors.lastname: Shin
authors.affiliation: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, United States. Electronic address: gskwon@pharmacy.wisc.edu.
authors.forename: Glen S
authors.initials: GS
authors.lastname: Kwon
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D016227:Benzoquinones / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D004338:Drug Combinations; D065546:Drug Liberation; D034261:Epothilones / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D008819:Mice, Nude; D008823:Micelles; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D020123:Sirolimus / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D004338:Drug Combinations; D034261:Epothilones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008823:Micelles; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D011092:Polyethylene Glycols; C112765:tanespimycin; D058570:TOR Serine-Threonine Kinases; C093788:epothilone B; D020123:Sirolimus
keywords: Drug combination; Epothilone B; Multiple drug solubilization; Non-small cell lung cancer; Polymeric micelle