Lipophilic prodrugs of Hsp90 inhibitor geldanamycin for nanoencapsulation in poly(ethylene glycol)-b-poly(epsilon-caprolactone) micelles.
A solvent and Cremephor free formulation of the anticancer chemotherapeutic geldanamycin was prepared using amphiphilic block co-polymer 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, IC(50) 240 nM.
Forrest
M Laird
ML
Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705-2222, USA.
Zhao
Anni
A
Won
Chee-Youb
CY
Malick
A Waseem
AW
Kwon
Glen S
GS
D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D016227:Benzoquinones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004339:Drug Compounding / Q000379:methods; D015195:Drug Design; D005026:Ethylene Glycols / Q000737:chemistry*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007700:Kinetics; D047029:Lactams, Macrocyclic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008823:Micelles; D036103:Nanotechnology; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D012995:Solubility
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005026:Ethylene Glycols; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008823:Micelles; D011091:Polyesters; D011355:Prodrugs; C476300:poly(epsilon-caprolactone)-b-poly(ethylene glycol); C001277:geldanamycin