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CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing

Clark, Andrew J. and Wiley, Devin T. and Zuckerman, Jonathan E. and Webster, Paul and Chao, Joseph and Lin, James and Yen, Yun and Davis, Mark E. (2016) CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing. Proceedings of the National Academy of Sciences of the United States of America, 113 (14). pp. 3850-3854. ISSN 0027-8424. PMCID PMC4833237. http://resolver.caltech.edu/CaltechAUTHORS:20160321-153715728

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Abstract

Nanoparticle-based therapeutics are being used to treat patients with solid tumors. Whereas nanoparticles have been shown to preferentially accumulate in solid tumors of animal models, there is little evidence to prove that intact nanoparticles localize to solid tumors of humans when systemically administered. Here, tumor and adjacent, nonneoplastic tissue biopsies are obtained through endoscopic capture from patients with gastric, gastroesophageal, or esophageal cancer who are administered the nanoparticle CRLX101. Both the pre- and postdosing tissue samples adjacent to tumors show no definitive evidence of either the nanoparticle or its drug payload (camptothecin, CPT) contained within the nanoparticle. Similar results are obtained from the predosing tumor samples. However, in nine of nine patients that were evaluated, CPT is detected in the tumor tissue collected 24–48 h after CRLX101 administration. For five of these patients, evidence of the intact deposition of CRLX101 nanoparticles in the tumor tissue is obtained. Indications of CPT pharmacodynamics from tumor biomarkers such as carbonic anhydrase IX and topoisomerase I by immunohistochemistry show clear evidence of biological activity from the delivered CPT in the posttreatment tumors.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1603018113 DOIArticle
http://www.pnas.org/content/113/14/3850PublisherArticle
http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1603018113/-/DCSupplementalPublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833237/PubMed CentralArticle
Additional Information:© 2016 National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Mark E. Davis, February 23, 2016 (sent for review February 3, 2016; reviewed by Omid Farokhzad and David V. Schaffer). Published online before print March 21, 2016. We thank the patients and families who participated in this study. This work was supported by National Cancer Institute Grants CA 151819 and L30 CA179788-01, National Institutes of Health Grant 2K12CA001727-21, and by Cerulean Pharma Inc. Author contributions: A.J.C., D.T.W., J.E.Z., P.W., J.C., Y.Y., and M.E.D. designed research; A.J.C., D.T.W., J.E.Z., P.W., J.C., and J.L. performed research; A.J.C., D.T.W., J.E.Z., P.W., J.C., Y.Y., and M.E.D. analyzed data; and A.J.C., J.E.Z., Y.Y., and M.E.D. wrote the paper. Reviewers: O.F., Harvard Medical School; and D.V.S., University of California, Berkeley. Conflict of interest statement: M.E.D. is a consultant to Cerulean Pharma Inc. and owns stock in the company. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1603018113/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
National Cancer InstituteCA 151819
National Cancer InstituteL30 CA179788-01
NIH2K12CA001727-21
Cerulean Pharma Inc.UNSPECIFIED
Subject Keywords:nanomedicine; clinical trial; gastric cancer; tumor targeting; nanoparticles
PubMed Central ID:PMC4833237
Record Number:CaltechAUTHORS:20160321-153715728
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20160321-153715728
Official Citation:Andrew J. Clark, Devin T. Wiley, Jonathan E. Zuckerman, Paul Webster, Joseph Chao, James Lin, Yun Yen, and Mark E. Davis CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing PNAS 2016 113 (14) 3850-3854; published ahead of print March 21, 2016, doi:10.1073/pnas.1603018113
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:65562
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Mar 2016 22:56
Last Modified:19 Jul 2017 22:28

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