Design and evaluation of micellar nanocarriers for 17-allyamino-17-demethoxygeldanamycin (17-AAG)

• Published in: International journal of pharmaceutics Vol. 392; no. 1; pp. 170 - 177
• Main Authors: Chandran, Thripthy, Katragadda, Usha, Teng, Quincy, Tan, Chalet
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 15-06-2010; Elsevier
• Subjects: 17-AAG; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Benzoquinones - administration & dosage; Benzoquinones - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chromatography, High Pressure Liquid; Delayed-Action Preparations; Drug Carriers - chemistry; Drug Design; Drug Evaluation, Preclinical; Drug release; Drug Stability; Drug Storage; General pharmacology; Humans; Lactams, Macrocyclic - administration & dosage; Lactams, Macrocyclic - pharmacology; Magnetic Resonance Spectroscopy; Medical sciences; Micelles; Nanoparticles - chemistry; Particle Size; PEG-DSPE; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Phosphatidylethanolamines - chemistry; Polyethylene Glycols - chemistry; Polymeric micelles; Solubility; TPGS; Vitamin E - chemistry; Drug release; PEG-DSPE; 17-AAG; Polymeric micelles; TPGS; Evaluation; Pharmaceutical technology; Control release polymer; Micelle; Drug carrier; Design; Ethylene oxide polymer; Cyclic ether polymer; Nanotechnology
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2010.03.056

17-Allyamino-17-demethoxygeldanamycin (17-AAG) is a potent anticancer agent currently undergoing phases I and II clinical trials. However, the clinical development of 17-AAG has been hindered by its poor aqueous solubility and hepatotoxicity. This study aimed to devise novel micellar nanocarriers for 17-AAG that improve its solubility and retain the incorporated drug for a prolonged period of time. We have found that 1,2-distearoyl-
sn-glycero-3-phosphoethanolamine-
N-[methoxy(polyethylene glycol)-2000]/
d-α-tocopheryl polyethylene glycol 1000 (PEG-DSPE/TPGS) mixed micelles (at a 1:2 molar ratio) can deliver 17-AAG at clinically relevant doses. By modulating the concentrations of micelle-forming copolymers, the burst release of 17-AAG from PEG-DSPE/TPGS mixed micelles was substantially reduced with a release half-life up to about 8
h. Our
1H NMR spectroscopy results revealed that the incorporation of TPGS into PEG-DSPE micelles restricted internal molecular motions of copolymers in both the corona and core regions of the micelles, leading to the delayed drug release. Cytotoxicity of 17-AAG formulated in PEG-DSPE/TPGS mixed micelles against human ovarian cancer SKOV-3 cells was comparable to that of free 17-AAG. 17-AAG-loaded PEG-DSPE/TPGS mixed micelles may offer a promising alternative to the current 17-AAG formulations for the treatment of solid tumors.