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

Abstract

The histone deacetylase inhibitor suberoylanilide hydroxamic acid, known as vorinostat, is a promising anti-cancer drug with a unique mode of action; however, it is plagued by low water solubility, low permeability, and suboptimal pharmacokinetics. In this study, poly(ethylene glycol)-b-poly(DL-lactic acid) (PEG-b-PLA) micelles of vorinostat were developed. Vorinostat’s pharmacokinetics in rats were investigated after intravenous (i.v.) (10 mg/kg) and oral (50 mg/kg) micellar administrations and compared to a conventional PEG400 solution and methylcellulose suspension. The micelles increased the aqueous solubility of vorinostat from 0.2 mg/ml to 8.15 ± 0.60 mg/ml and 10.24 ± 0.92 mg/ml at drug to nanocarrier ratios of 1:10 and 1:15, respectively. Micelles had nanoscopic mean diameters of 75.67 ± 7.57 nm and 87.33 ± 8.62 nm for 1:10 and 1:15 micelles, respectively, with drug loading capacities of 9.93 ± 0.21% and 6.91 ± 1.19 %, and encapsulation efficiencies of 42.74 ± 1.67% and 73.29 ± 4.78%, respectively. The micelles provided sustained exposure and improved pharmacokinetics characterized by a significant increase in serum half-life, area under curve, and mean residence time. The micelles reduced vorinostat clearance particularly after i.v. dosing. Thus, PEG-b-PLA micelles significantly improved the oral and intravenous pharmacokinetics and bioavailability of vorinostat, which warrants further investigation.

PEG- b -PLA micelles and PLGA- b -PEG- b -PLGA sol–gels for drug delivery

“…However, Taxotere ® caused hypersensitivity reactions and fluid retention in beagle dogs, whereas Nonoxel-PM ™ has no such effects in beagle dogs. Interestingly, PEG- b -PLA micelles did significantly modify the pharmacokinetic parameters of vorinostat, an HDAC inhibitor, compared to a conventional formulation of PEG400 in rats [29]: Mean residence time increased by two orders of magnitude, dramatically increasing exposure of vorinostat. It is noted that the molecular weight of PEG and PLA was relatively high, ca.…”

Nanoparticulate immunotherapy for cancer

“…Recently, much effort has been devoted to designing delivery carriers for vorinostat (HDACi), for example using copolymer micelles of poly (ethylene oxide) (PEO)-polylactic acid (PLA). These carriers have improved vorinostat solubility up to 40-fold, improved the pharmacokinetics, extended circulation half-life, and decreased clearance [140,141]. Furthermore, the therapeutic index of vorinostat was improved by developing acid sensitive delivery system out of a pro-drug of vorinostat [142].…”

Iron Complexation to Histone Deacetylase Inhibitors SAHA and LAQ824 in PEGylated Liposomes Can Considerably Improve Pharmacokinetics in Rats

“…administration remains a challenge due to their limited aqueous solubility and poor PK in vivo (10, 11). To address these challenges, a recent study has reported on the use of poly(ethylene glycol)-b-poly(DL-lactic acid) (PEG-b-PLA) micelles to encapsulate SAHA to improve both solubility and PK of the drug (12). In another example, LAQ was successfully entrapped into targeted immunoliposomes via formation of a complex between LAQ and a polymer, polyanionic polyol sucrose octasulfate (SOS), resulting in prolonged PK and improved antitumor properties (13).…”