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In vitro macrophage uptake and in vivo biodistribution of PLA–PEG nanoparticles loaded with hemoglobin as blood substitutes: effect of PEG content

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Abstract

The aim of the present work is to investigate the effect of PEG content in copolymer on physicochemical properties, in vitro macrophage uptake, in vivo pharmacokinetics and biodistribution of poly(lactic acid) (PLA)–poly(ethylene glycol) (PEG) hemoglobin (Hb)-loaded nanoparticles (HbP) used as blood substitutes. The HbP were prepared from PLA and PLA–PEG copolymer of varying PEG contents (5, 10, and 20 wt%) by a modified w/o/w method and characterized with regard to their morphology, size, surface charge, drug loading, surface hydrophilicity, and PEG coating efficiency. The in vitro macrophage uptake, in vivo pharmacokinetics, and biodistribution following intravenous administration in mice of HbP labeled with 6-coumarin, were evaluated. The HbP prepared were all in the range of 100–200 nm with highest encapsulation efficiency 87.89%, surface charge −10 to −33 mV, static contact angle from 54.25° to 68.27°, and PEG coating efficiency higher than 80%. Compared with PLA HbP, PEGylation could notably avoid the macrophage uptake of HbP, in particular when the PEG content was 10 wt%, a minimum uptake (6.76%) was achieved after 1 h cultivation. In vivo, besides plasma, the major cumulative organ was the liver. All PLA–PEG HbP exhibited dramatically prolonged blood circulation and reduced liver accumulation, compared with the corresponding PLA HbP. The PEG content in copolymer affected significantly the survival time in blood. Optimum PEG coating (10 wt%) appeared to exist leading to the most prolonged blood circulation of PLA–PEG HbP, with a half-life of 34.3 h, much longer than that obtained by others (24.2 h). These results demonstrated that PEG 10 wt% modified PLA HbP with suitable size, surface charge, and surface hydrophilicity, has a promising potential as long-circulating oxygen carriers with desirable biocompatibility and biofunctionality.

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Acknowledgments

The authors acknowledge the financial support from the National High Technology Research and Development Program of China (863 program) (No. 2004AA-302050) and from Shanghai Nanotechnology Special Foundation (No. 0452nm022).

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Authors and Affiliations

  1. The State Key Laboratory of Bioreactor Engineering, Key Laboratory for Ultrafine Materials of Ministry of Education, and Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Mailbox 112, 130 Meilong Road, Xuhui District, Shanghai, 200237, People’s Republic of China

    Yan Sheng, Yuan Yuan, Changsheng Liu, Xinyi Tao, Xiaoqian Shan & Feng Xu

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  1. Yan Sheng
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Correspondence to Changsheng Liu.

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Sheng, Y., Yuan, Y., Liu, C. et al. In vitro macrophage uptake and in vivo biodistribution of PLA–PEG nanoparticles loaded with hemoglobin as blood substitutes: effect of PEG content. J Mater Sci: Mater Med 20, 1881–1891 (2009). https://doi.org/10.1007/s10856-009-3746-9

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