Enhancement of oral bioavailability of doxorubicin through surface modified biodegradable polymeric nanoparticles

摘要

Background: Doxorubicin hydrochloride (DOX·HCl), an anthracycline glycoside antibiotic, exhibits low oral bioavailability due to active efux from intestinal P-glycoprotein receptors. The oral administration of DOX remains a challengehence; no oral formulation for DOX is marketed, till date.Aim of the study: To improve the oral bioavailability of DOX through, preparation of a nanoformulation i.e.PEGylated-doxorubicin(DOX)-loaded-poly-lactic-co-glycolic acid (PLGA)-Nanoparticles (NPs) and to develop and validate an ultra-high performance liquid chromatography electrospray ionization-synapt mass spectrometric bioanalytical method (UHPLC/ESI-QTOF–MS/MS) for plasma (Wistar rats) DOX quantifcation.Materials and methods: For chromatography, Waters ACQUITY UPLC? along with a BEH C-18 column(2.1 mm× 100 mm; 1.7 μm), mobile phase conditions (acetonitrile: 0.1% formic acid::1:1 v/v) and fow rate (0.20 ml/min) was used. For analyte recovery from rat plasma, a liquid–liquid extraction method (LLE), using Acetonitrile: 5 mMammonium acetate in a ratio of 6:4 v/v at pH 3.5, was used.Results: Nanoformulation with a particle size (183.10± 7.41 nm), zeta potential (? 13.10± 1.04 mV), drug content(42.69± 1.97 μg/mg) and a spherical shape and smooth surface was developed. An elution time of 1.61 and 1.75 minalong with a transition at m/z 544.42/397.27 and 528.46/321.41 were observed for DOX and internal standard (IS)Daunorubicin, respectively. In addition, a linear dynamic range with r2≥ 0.9985 over a concentration range of 1.00–2500.0 ng/ml was observed for diferent processes and parameters used in the study. Similarly a marked improvementi.e. 6.8 fold was observed, in PEGylated-DOX-PLGA-NPs as compared to DOX-S, in pharmacokinetics studies.Conclusion: The promising approach of PEGylated-DOX-PLGA-NPs may provide an alternate to intravenous therapyfor better patient care.