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: Ho-Chul Shin, Adam W G Alani, Hyunah Cho, Younsoo Bae, Jill M Kolesar, Glen S Kwon
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 8 Issue 4 Pg. 1257-65 (Aug 01 2011) ISSN: 1543-8392 [Electronic] United States
• PMID: 21630670 (Publication Type: Journal Article)

Chemical References

• Benzoquinones
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• Micelles
• Polyesters
• Polymers
• Water
• Lactic Acid
• Polyethylene Glycols
• poly(lactide)
• tanespimycin
• TOR Serine-Threonine Kinases
• Paclitaxel
• Sirolimus

Topics

• Benzoquinones (chemistry)
• Cell Line, Tumor
• HSP90 Heat-Shock Proteins (chemistry)
• Humans
• Lactams, Macrocyclic (chemistry)
• Lactic Acid (chemistry)
• Micelles
• Models, Theoretical
• Paclitaxel (chemistry)
• Polyesters
• Polyethylene Glycols (chemistry)
• Polymers (chemistry)
• Sirolimus (chemistry)
• Solubility
• TOR Serine-Threonine Kinases (chemistry)
• Water (chemistry)