Original Article
In vivo efficacy and pharmacokinetics of bi-aryl oxazolidinone RBx 11760 loaded polylactic acid–polyethylene glycol nanoparticles in mouse hematogenous bronchopneumonia and rat groin abscess caused by Staphylococcus aureus

https://doi.org/10.1016/j.nano.2018.02.003Get rights and content

Abstract

RBx 11760 is a bi-aryl oxazolidinone antibacterial agent active against Staphylococcus aureus but has poor solubility. Here we have encapsulated RBx 11760 in PLA–PEG NPs with an aim to improve physicochemical, pharmacokinetics and in vivo efficacy. The average size and zeta potential of RBx 11760 loaded NPs were found to be 106.4 nm and −22.2 mV, respectively. The absolute size of nanoparticles by HRTEM was found to be approximately 80 nm. In vitro antibacterial agar well diffusion assay showed clear zone of inhibition of bacterial growth. In pharmacokinetic study, nanoparticle showed 4.6-fold and 7-fold increase in AUCinf and half-life, respectively, as compared to free drug. RBx 11760 nanoparticle significantly reduced bacterial counts in lungs and improved the survival rate of immunocompromised mice as compared to free drugs. Thus, RBx 11760 loaded nanoparticles have strong potential to be used as nanomedicine against sensitive and drug resistant Staphylococcus aureus infections.

Graphical Abstract

RBx 11760 is a promising investigational antibacterial agent active against Gram positive bacteria with poor solubility.

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    RBx 11760 loaded PLA72K-PEG4K NPs as compared to its free form demonstrated an equivalent in vitro activity.

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    It exhibited potent in vivo efficacy in mice model of bronchopneumonia and in rat model of groin abscess.

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    The pharmacokinetic-pharmacodynamic parameters of RBx 11760 nanoparticles such as prolong half life, higher AUC, effective T>MIC and sustained release in mice were correlated well with the in vivo efficacy.

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    Thus, RBx 11760 NPs have strong potential to be used as nanomedicine.

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Section snippets

Methods

The details of the materials and methods are given in the Supplementary material.

Synthesis and characterization of PLA72K-PEG4K block copolymer

PLA72K–PEG4K block copolymers were synthesized by the DCC/DMAP conjugation method. As determined by GPC, PLA–PEG block copolymer showed molecular weight average (Mw) of 73,054 and 4802 for PLA72K and PEG4K, respectively with polydispersity index (PI) of 1.08 (Table 1). The FTIR spectra of PLA revealed a prominent peak at 1757 and 1089 cm−1 attributed to the carbonyl (-C=O) and C-O stretching frequency of the carboxylic acid group of PLA. Concomitantly, at 1455 and 1360 cm−1 bending frequency of

Discussion

The challenges of developing new drug are difficult lead optimisation process encompassing physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties to get desired pharmacodynamics. Majority of new chemical entities (NCEs) have failed to be developed due to poor ADME and physicochemical properties.36, 37 Solubility of NCEs is one of the critical success factors which greatly affect the development of clinical formulations.38, 39 As a rapidly developing area,

Acknowledgements

The facilities availed from All India Institute of Medical Sciences (AIIMS), Analytical and Bio-analytical section Daiichi Sankyo India Pharma Private limited, Biomaterials Laboratory, Centre for Biomedical Engineering, IIT Delhi and Central facility, IIT Delhi are duly acknowledged.

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    • Cited by (0)

    We thank Daiichi Sankyo India Pharma Private Limited, Gurgaon and Indian Institute of Technology, Hauz Khas, New Delhi, India for financial support for this study. All authors declare that they have no conflict of interests.

    1

    Present address: Department of development and regeneration, Stem cell institute, KU Leuven, Belgium.

    2

    Present address: Center for Drug Design Discovery and Development (C4D), SRM University Haryana, Sonepat, Haryana-131,029, India.

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