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

Eliasof, Scott and Lazarus, Douglas and Peters, Christian G. and Case, Roy I. and Cole, Roderic O. and Hwang, Jungyeon and Schluep, Thomas and Chao, Joseph and Lin, James and Yen, Yun and Han, Han and Wiley, Devin T. and Zuckerman, Jonathan E. and Davis, Mark 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). pp. 15127-15132. ISSN 0027-8424. PMCID PMC3773776. doi:10.1073/pnas.1309566110.

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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 consistent with 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.

Item Type:Article
Related URLs:
URLURL TypeDescription DOIArticle CentralArticle
Yen, Yun0000-0003-0815-412X
Davis, Mark E.0000-0001-8294-1477
Additional Information:© 2013 National Academy of Sciences. Edited by Joseph M. DeSimone, The University of North Carolina at Chapel Hill, Chapel Hill, NC, and approved July 30, 2013 (received for review May 20, 2013). Published online before print August 26, 2013. We thank Alasdair McDowall [Director of the electron microscopy facility in the Jensen laboratory at the California Institute of Technology (Caltech)] for his help in obtaining the cryo-TEM images. The work at Caltech was financially supported by National Cancer Institute Grant CA 151819. The electron microscopy facility in the Jensen laboratory at California Institute of Technology is supported in part by the Gordon and Betty Moore Foundation, the Agouron Institute, and the Beckman Foundation at Caltech.
Funding AgencyGrant Number
NIHCA 151819
Gordon and Betty Moore FoundationUNSPECIFIED
Agouron InstituteUNSPECIFIED
Arnold and Mabel Beckman FoundationUNSPECIFIED
National Cancer InstituteUNSPECIFIED
Subject Keywords:nanomedicine; clinical translation; interspecies scaling; pharmacodynamics; Nanoparticles
Issue or Number:37
PubMed Central ID:PMC3773776
Record Number:CaltechAUTHORS:20131011-092434485
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:41886
Deposited By: Tony Diaz
Deposited On:11 Oct 2013 17:23
Last Modified:10 Nov 2021 04:35

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