Lipophilic prodrugs of Hsp90 inhibitor geldanamycin for nanoencapsulation in poly(ethylene glycol)-b-poly(ε-caprolactone) micelles

A solvent and Cremephor (R) free, formulation of the anticancer chemotherapeutic geldanamycin was prepared using amphiphilic block copolymer micelles of poly(ethylene glycol)-b-poly(epsilon-caprolactone) (PEG-b-PCL). Although geldanamycin was not solubilized by PEG-b-PCL micelles, fatty acid prodrugs of geldanamycin were encapsulated in PEG-b-PCL micelles by a co-solvent extraction technique. Resulting PEG-b-PCL micelles were < 120 nm in diameter and solubilized > 20% w/w geldanamycin prodrugs increasing aqueous solubility to > 2 mg/mL. PEG-b-PCL micelles released the geldanamycin prodrugs over several days, t(1/2) 2.2 to 9.6 days. The free prodrugs hydrolyzed rapidly, t(1/2) < 6 h, into the geldanamycin analogue 17-beta-hydroxyethylamino-17-demethoxygeldanamycin, which has high activity against MCF-7 breast cancer cells, IC50 240 nM. (c) 2006 Elsevier B.V. All rights reserved.