Abstract
BackgroundDoxorubicin hydrochloride (DOX·HCl), an anthracycline glycoside antibiotic, exhibits low oral bioavailability due to active efflux from intestinal P-glycoprotein receptors. The oral administration of DOX remains a challenge hence; no oral formulation for DOX is marketed, till date.Aim of the studyTo 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 quantification.Materials and methodsFor 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 flow rate (0.20 ml/min) was used. For analyte recovery from rat plasma, a liquid–liquid extraction method (LLE), using Acetonitrile: 5 mM ammonium acetate in a ratio of 6:4 v/v at pH 3.5, was used.ResultsNanoformulation 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 min along 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 different processes and parameters used in the study. Similarly a marked improvement i.e. 6.8 fold was observed, in PEGylated-DOX-PLGA-NPs as compared to DOX-S, in pharmacokinetics studies.ConclusionThe promising approach of PEGylated-DOX-PLGA-NPs may provide an alternate to intravenous therapy for better patient care.
Highlights
Doxorubicin hydrochloride (DOX·HCl), have been reported with a widespread applications in ovarian, breast and lung cancer as well as malignant lymphoma [1, 2] the cardiotoxicity associated side effect limits its long term use for such clinical purposes [3, 4]
An elution time of 1.61 and 1.75 min along 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
The promising approach of PEGylated-DOX-poly-lactic-co-glycolic acid (PLGA)-NPs may provide an alternate to intravenous therapy for better patient care
Summary
Doxorubicin hydrochloride (DOX·HCl), have been reported with a widespread applications in ovarian, breast and lung cancer as well as malignant lymphoma [1, 2] the cardiotoxicity associated side effect limits its long term use for such clinical purposes [3, 4]. PEG-decorated NPs have been reported to have a high diffusion property and penetration across thick layer of mucosa [21, 31] and an additive bio adhesive property [32, 33] which imparts the property of enhanced oral bioavailability as compared to non-PEGylated particles [21, 34]. In the study, PEGylated– PLGA-NPs for DOX (DOX-PEG-PLGA-PNPs), available in injectable form only for commercial purposes, will be developed and the surface-decoration-effects upon the PK and PD behavior of developed NPs will be evaluated. In addition to nanoparticle approaches, lack of improper less selective and sensitive method of quantification makes it difficult to measure DOX concentration in any biological samples, following oral administration. A liquid chromatography/electrospray tandem mass spectrometry for quantification of PEG-liposomal-DOX was developed by Arnold et al [41], lack of selectivity was observed for the method. The oral administration of DOX remains a challenge ; no oral formulation for DOX is marketed, till date
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