Formulation of a geldanamycin prodrug in mPEG-b-PCL micelles greatly enhances tolerability and pharmacokinetics in rats

Abstract

Geldanamycin (GA) and its analogues inhibit heat shock protein 90 (Hsp90) and have shown significant antitumor activity in vivo; however, clinical development of GA has been hampered by its poor solubility and severe hepatotoxicity. More soluble analogues, such as 17-DMAG and 17-AAG, are easier to formulate, and have progressed through early clinical trials. However the large volume of distribution and systemic toxicity associated with these analogues may limit their distribution into tumors, thereby severely reducing efficacy and increasing nonspecific toxicities. We have evaluated a formulation of a lipophilic GA prodrug, 17′GAC 16 Br encapsulated in methoxycapped poly(ethylene glycol)-block-poly(ε-caprolactone) (mPEG-b-PCL) micelles, by comparing it to free 17-DMAG at 10 mg/kg in rats. mPEG-b-PCL micelles reported herein demonstrated substantial sustained release and conversion of 17′GAC 16 Br into 17′GAOH at significantly greater levels in all tissues analyzed compared to the free drug, allowing for a 72-fold enhancement in the AUC, a 21-fold decrease in V d , an 11-fold decrease in CL tot , and a 2-fold and 7-fold enhancement in the overall MRT of 17′GAC 16 Br and 17′GAOH, respectively. Importantly, the micellar formulation exhibited lower systemic toxicity than 17-DMAG, with a MTD > 200 mg/kg and a 2000-fold enhancement in the AUC. 17′GAC 16 Br in micelles were poorly cleared renally, in contrast to 17-DMAG and 17′GAOH, but showed preferential accumulation and prodrug conversion in reticuloendothelial organs of normal animals. Overall, the data indicates that this nanocarrier system is a promising alternative to the current 17-DMAG formulation and offers excellent potential for further pre-clinical and clinical cancer studies.

Vorinostat with sustained exposure and high solubility in poly(ethylene glycol)‐b‐poly(dl‐lactic acid) micelle nanocarriers: Characterization and effects on pharmacokinetics in rat serum and urine

“…The day before the pharmacokinetic experiment, the right jugular veins of the rats were catheterized with sterile silastic cannula (Dow Corning, Midland, MI, USA) under isoflurane anesthesia via procedures previously published. 28 This involved exposure of the vessel prior to cannula insertion. After cannulation, Intramedic PE-50 polyethylene tubing (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) connected to the cannula was exteriorized through the dorsal skin.…”

Nanomicellar Formulations for Sustained Drug Delivery: Strategies and Underlying Principles

“…Apart from increasing the release time and effect, this approach may lead to an increase in tolerability of the drugs among drug recipients. Another study by Xiong et al showed an increase in tolerability towards geldanamycin prodrug in rats when formulated in methoxy PEG-b-PCL (5000:9200) micelles [10]. Free prodrug was administered to Sprague Dawley rats at 10, 20 and 40 mg/kg doses and prodrug encapsulated in micelles was administered at 10, 20, 40, and 200 mg/kg doses.…”

Nanoparticle-mediated delivery of a rapidly activatable prodrug of SN-38 for neuroblastoma therapy

“…Directed changes in the drug molecular structure aimed at forming bioreversible precursors (prodrugs) with increased affinity for the carrier have been explored as a means of preventing premature drug dissociation [11–14]. However, the effective use of the prodrug approach poses an additional set of challenges, because the kinetics of prodrug release and subsequent parent compound activation need to be tightly coordinated with that of the NP biodistribution.…”