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Effective Targeting of Liposomes to Liver and Hepatocytes In Vivo by Incorporation of a Plasmodium Amino Acid Sequence

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Purpose

Several species of the protozoan Plasmodium effectively target mammalian liver during the initial phase of host invasion. The purpose of this study was to demonstrate that a Plasmodium targeting amino acid sequence can be engineered into therapeutic nanoparticle delivery systems.

Methods

A 19-amino peptide from the circumsporozoite protein of Plasmodium berghei was prepared containing the conserved region I as well as a consensus heparan sulfate proteoglycan binding sequence. This peptide was attached to the distal end of a lipid–polyethylene glycol bioconjugate. The bioconjugate was incorporated into phosphatidylcholine liposomes containing fluorescently labeled lipids to follow blood clearance and organ distribution in vivo.

Results

When administered intravenously into mice, the peptide-containing liposomes were rapidly cleared from the circulation and were recovered almost entirely in the liver. Fluorescence and electron microscopy demonstrated that the liposomes were accumulated both by nonparenchymal cells and hepatocytes, with the majority of the liposomal material associated with hepatocytes. Accumulation of liposomes in the liver was several hundredfold higher compared to heart, lung, and kidney, and more than 10-fold higher compared to spleen. In liver slice experiments, liposome binding was specific to sites sensitive to heparinase.

Conclusions

Incorporation of amino acid sequences that recognize glycosaminoglycans is an effective strategy for the development of targeted drug delivery systems.

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Abbreviations

ASGP-R:

asialoglycoprotein receptor

CSP:

circumsporozoite protein

HSPG:

heparan sulfate proteoglycan

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Acknowledgments

This work was supported by the National Institutes of Health EB-003075. The authors thank Dr. E. Wisse for his very informative personal communications regarding liver anatomy and fine structure.

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Correspondence to Kenneth J. Longmuir.

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K. J. Longmuir and R. T. Robertson were the primary investigators for this study.

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Longmuir, K.J., Robertson, R.T., Haynes, S.M. et al. Effective Targeting of Liposomes to Liver and Hepatocytes In Vivo by Incorporation of a Plasmodium Amino Acid Sequence. Pharm Res 23, 759–769 (2006). https://doi.org/10.1007/s11095-006-9609-x

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