Altered Biodistribution and Tissue Retention of Nanoparticles Targeted with P-Glycoprotein Substrates

Abstract

Low molecular weight substrates of the efflux transporter, P-glycoprotein, alter the biodistribution and tissue retention of nanoparticles following intravenous administration. Of particular interest is the retention of the targeted nanoparticles in the brain. Drug delivery to the brain is hindered by the restricted transport of drugs through the blood-brain barrier (BBB). Drugs that passively diffuse across the BBB also have large volumes of distribution; therefore, alteration of their biodistribution to increase their concentration in the brain may help to enhance efficacy and reduce off-target side effects. In this work, targeted nanoparticles were used to explore a new approach to target drugs to the brain—the exploitation of the P-glycoprotein efflux pump. The retention of nanoparticles containing a strong P-glycoprotein substrate, rhodamine 6G, tethered to a PLA nanoparticle through a PEG spacer was greater than twofold relative to untargeted nanoparticles and to nanoparticles tethered to a weaker P-glycoprotein substrate, rhodamine 123. In a P-glycoprotein knockout mouse model (mdr1a (-/-)), there were no significant differences in brain accumulation between rhodamine 6G-targeted particles and controls, strongly supporting the role of P-glycoprotein. This proof of concept report shows the potential applicability of low molecular weight P-gp substrates to alter nanoparticle biodistribution.

Lay Summary

The efficacy of medicines can be improved by diverting drugs to specific tissues. Finding new ways to target medicines to diseased tissue is an active area of research across disciplines. Drug-loaded nanoparticles, delivered to tissues of interest, are one way to accomplish this goal. The work reported in this manuscript explores the possibility of using small molecules to get nanoparticles to bind to a drug efflux pump, P-glycoprotein (P-gp), that is present in various tissues in the body. P-gp functions to remove drugs from tissues, and it is usually considered a hindrance to drug targeting. The research in this paper shows that the natural function of P-gp can be used favorably to retain nanoparticles in various tissues.

Future Work

The data reported in this manuscript serves to establish a proof-of-concept that low molecular weight P-gp substrates can be used to alter the biodistribution of nanoparticles. Future work includes (1) understanding the targeting mechanism(s) that lead to these results, (2) identifying FDA-approved drugs that can target nanoparticles, and (3) evaluating how nanoparticle biodistribution is altered by using P-gp substrates with different binding constants.

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Acknowledgments

This work was made possible by a Graduate Fellowship to L.C. from the National Science Foundation. We particularly thank Prof. Bill Brown in the Department of Molecular Biology & Genetics at Cornell for use of his ultracentrifuge. This work made use of the Cornell Center for Materials Research Shared Facilities, which are supported through the NSF MRSEC program (DMR-1719875).

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Correspondence to David Putnam.

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All research involving animals was conducted under IACUC approval at Cornell University. Specific approved protocol numbers are provided in the text of the manuscript in the relevant sections.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Crawford, L.A., Watkins, H.C., Wayne, E. et al. Altered Biodistribution and Tissue Retention of Nanoparticles Targeted with P-Glycoprotein Substrates. Regen. Eng. Transl. Med. 5, 308–318 (2019). https://doi.org/10.1007/s40883-019-00111-8

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Keywords

  • Drug targeting
  • Nanoparticles
  • P-glycoprotein
  • Blood-brain barrier