CaltechAUTHORS
  A Caltech Library Service

Pharmacokinetics and tumor dynamics of the nanoparticle IT-101 from PET imaging and tumor histological measurements

Schluep, Thomas and Hwang, Jungyeon and Hildebrandt, Isabel J. and Czernin, Johannes and Choi, Chung Hang J. and Alabi, Christopher A. and Mack, Brendan C. and Davis, Mark E. (2009) Pharmacokinetics and tumor dynamics of the nanoparticle IT-101 from PET imaging and tumor histological measurements. Proceedings of the National Academy of Sciences of the United States of America, 106 (27). pp. 11394-11399. ISSN 0027-8424. PMCID PMC2703672. doi:10.1073/pnas.0905487106. https://resolver.caltech.edu/CaltechAUTHORS:20090825-134717535

[img]
Preview
PDF - Published Version
See Usage Policy.

756kB
[img]
Preview
PDF - Supplemental Material
See Usage Policy.

1MB

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20090825-134717535

Abstract

IT-101, a cyclodextrin polymer-based nanoparticle containing camptothecin, is in clinical development for the treatment of cancer. Multiorgan pharmacokinetics and accumulation in tumor tissue of IT-101 is investigated by using PET. IT-101 is modified through the attachment of a 1,4,7,10-tetraazacyclododecane-1,4,7-Tris-acetic acid ligand to bind ^(64)Cu^(2+). This modification does not affect the particle size and minimally affects the surface charge of the resulting nanoparticles. PET data from ^(64)Cu-labeled IT-101 are used to quantify the in vivo biodistribution in mice bearing Neuro2A s.c. tumors. The ^(64)Cu-labeled IT-101 displays a biphasic plasma elimination. Approximately 8% of the injected dose is rapidly cleared as a low-molecular-weight fraction through the kidneys. The remaining material circulates in plasma with a terminal half-life of 13.3 h. Steadily increasing concentrations, up to 11% injected dose per cm^3, are observed in the tumor over 24 h, higher than any other tissue at that time. A 3-compartment model is used to determine vascular permeability and nanoparticle retention in tumors, and is able to accurately represent the experimental data. The calculated tumor vascular permeability indicates that the majority of nanoparticles stay intact in circulation and do not disassemble into individual polymer strands. A key assumption to modeling the tumor dynamics is that there is a “sink” for the nanoparticles within the tumor. Histological measurements using confocal microscopy show that IT-101 localizes within tumor cells and provides the sink in the tumor for the nanoparticles.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.0905487106DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2703672/PubMed CentralArticle
http://www.pnas.org/cgi/content/full/0905487106/DCSupplementalPublisherSupporting Information
ORCID:
AuthorORCID
Alabi, Christopher A.0000-0003-2654-018X
Davis, Mark E.0000-0001-8294-1477
Additional Information:© 2009 by the National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Mark E. Davis, May 20, 2009 (received for review April 24, 2009). Published online before print June 29, 2009, doi: 10.1073/pnas.0905487106 This work was supported in part by the National Cancer Institute Grant CA 119347. Author contributions: T.S., J.C., and M.E.D. designed research; J.H., I.J.H., C.H.J.C., C.A.A., and B.C.M. performed research; T.S., I.J.H., J.C., and M.E.D. analyzed data; and T.S. and M.E.D. wrote the paper. Conflict of interest statement: M.E.D. was but is no longer a consultant to Calando Pharmaceuticals. This article contains supporting information online at www.pnas.org/cgi/content/full/0905487106/DCSupplemental.
Funders:
Funding AgencyGrant Number
NIHCA 119347
National Cancer InstituteUNSPECIFIED
Subject Keywords:cancer; camptothecin; cyclodextrin; polymer; intracellular delivery
Issue or Number:27
PubMed Central ID:PMC2703672
DOI:10.1073/pnas.0905487106
Record Number:CaltechAUTHORS:20090825-134717535
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20090825-134717535
Official Citation:Pharmacokinetics and tumor dynamics of the nanoparticle IT-101 from PET imaging and tumor histological measurements Thomas Schluep, Jungyeon Hwang, Isabel J. Hildebrandt, Johannes Czernin, Chung Hang J. Choi, Christopher A. Alabi, Brendan C. Mack, Mark E. Davis Proceedings of the National Academy of Sciences Jul 2009, 106 (27) 11394-11399; DOI: 10.1073/pnas.0905487106
Usage Policy:Freely available online through the PNAS open access option.
ID Code:15302
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:08 Sep 2009 19:16
Last Modified:08 Nov 2021 23:18

Repository Staff Only: item control page