Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle

Scott Eliasof, Douglas Lazarus, Christian G. Peters, Roy I. Case, Roderic O. Cole, Jungyeon Hwang, Thomas Schluep, Joseph Chao, James Lin, Yun Yen, Han Han, Devin T. Wiley, Jonathan E. Zuckerman, Mark E. Davis

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Nanoparticles are currently being investigated in a number of human clinical trials. As information on how nanoparticles function in humans is difficult to obtain, animal studies that can be correlative to human behavior are needed to provide guidance for human clinical trials. Here, we report correlative studies on animals and humans for CRLX101, a 20- to 30-nm-diameter, multifunctional, polymeric nanoparticle containing camptothecin (CPT). CRLX101 is currently in phase 2 clinical trials, and human data from several of the clinical investigations are compared with results from multispecies animal studies. The pharmacokinetics of polymer-conjugated CPT (indicative of the CRLX101 nanoparticles) in mice, rats, dogs, and humans reveal that the area under the curve scales linearly with milligrams of CPT per square meter for all species. Plasma concentrations of unconjugated CPT released from CRLX101 in animals and humans are consistentwith each other after accounting for differences in serum albumin binding of CPT. Urinary excretion of polymer-conjugated CPT occurs primarily within the initial 24 h after dosing in animals and humans. The urinary excretion dynamics of polymer-conjugated and unconjugated CPT appear similar between animals and humans. CRLX101 accumulates into solid tumors and releases CPT over a period of several days to give inhibition of its target in animal xenograft models of cancer and in the tumors of humans. Taken in total, the evidence provided from animal models on the CRLX101 mechanism of action suggests that the behavior of CRLX101 in animals is translatable to humans.

Original languageEnglish
Pages (from-to)15127-15132
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number37
DOIs
Publication statusPublished - Sep 10 2013
Externally publishedYes

Keywords

  • Clinical translation
  • Interspecies scaling
  • Nanomedicine
  • Nanoparticles
  • Pharmacodynamics

ASJC Scopus subject areas

  • General

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  • Cite this

    Eliasof, S., Lazarus, D., Peters, C. G., Case, R. I., Cole, R. O., Hwang, J., Schluep, T., Chao, J., Lin, J., Yen, Y., Han, H., Wiley, D. T., Zuckerman, J. E., & Davis, M. E. (2013). Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle. Proceedings of the National Academy of Sciences of the United States of America, 110(37), 15127-15132. https://doi.org/10.1073/pnas.1309566110