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Enhancement of bioavailability by formulating rhEPO ionic complex with lysine into PEG–PLA micelle

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Abstract

A composite micelle of ionic complex encapsulated into poly(ethylene glycol)-poly(d,l-lactide) (PEG–PLA) di-block copolymeric micelles was used for protein drug delivery to improve its pharmacokinetic performance. In this study, recombinant human erythropoietin (rhEPO, as a model protein) was formulated with lysine into composite micelles at a diameter of 71.5 nm with narrow polydispersity indices (PDIs < 0.3). Only a trace amount of protein was in aggregate form. The zeta potential of the spherical micelles was ranging from −0.54 to 1.39 mv, and encapsulation efficiency is high (80 %). The stability of rhEPO was improved significantly in composite micelles in vitro. Pharmacokinetic studies in rats showed significant, enhanced plasma retention of the composite micelles in comparison with native rhEPO. Areas under curve (AUCs) of the rhEPO released from the composite micelles were 4.5- and 2.3-folds higher than those of the native rhEPO and rhEPO-loaded PEG–PLA micelle, respectively. In addition, the composite micelles exhibited good biocompatibility using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay with human embryonic kidney (HEK293T) cells. All these features are preferable for utilizing the composite micelles as a novel protein delivery system.

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Acknowledgments

This work was supported by the National Basic Research Program of China (No. 2012CB724003), the National Major Scientific and Technological Special Project for “Significant New Drugs Development” (No.2011ZX09501-001-04), and the National Key Technology Research and Development Program (No.2012BAK25B03).

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Authors and Affiliations

  1. College of Life Science, Jilin University, 2699 Qianjin Street, Changchun, China

    Yanan Shi, Fengying Sun, Dan Wang, Renyu Zhang & Youxin Li

  2. School of Pharmacy, Yantai University, 30 Qingquan Road, Yantai, China

    Changlin Dou, Wanhui Liu, Kaoxiang Sun & Youxin Li

  3. State Key Laboratory of Long-acting and Targeting Drug Delivery System, Luye Pharmaceutical Co. Ltd, 9 Baoyuan Road, Yantai, China

    Yanan Shi, Renyu Zhang, Changlin Dou, Wanhui Liu, Kaoxiang Sun & Youxin Li

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  1. Yanan Shi
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  2. Fengying Sun
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Correspondence to Kaoxiang Sun or Youxin Li.

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Yanan Shi and Fengying Sun contributed equally to this work.

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Shi, Y., Sun, F., Wang, D. et al. Enhancement of bioavailability by formulating rhEPO ionic complex with lysine into PEG–PLA micelle. J Nanopart Res 15, 2002 (2013). https://doi.org/10.1007/s11051-013-2002-x

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