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Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging

Bartlett, Derek W. and Su, Helen and Hildebrandt, Isabel J. and Weber, Wolfgang A. and Davis, Mark E. (2007) Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proceedings of the National Academy of Sciences of the United States of America, 104 (39). pp. 15549-15554. ISSN 0027-8424. PMCID PMC1978218. https://resolver.caltech.edu/CaltechAUTHORS:BARpnas07

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Abstract

Targeted delivery represents a promising approach for the development of safer and more effective therapeutics for oncology applications. Although macromolecules accumulate nonspecifically in tumors through the enhanced permeability and retention (EPR) effect, previous studies using nanoparticles to deliver chemotherapeutics or siRNA demonstrated that attachment of cell-specific targeting ligands to the surface of nanoparticles leads to enhanced potency relative to nontargeted formulations. Here, we use positron emission tomography (PET) and bioluminescent imaging to quantify the in vivo biodistribution and function of nanoparticles formed with cyclodextrin-containing polycations and siRNA. Conjugation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid to the 5' end of the siRNA molecules allows labeling with 64Cu for PET imaging. Bioluminescent imaging of mice bearing luciferase-expressing Neuro2A s.c. tumors before and after PET imaging enables correlation of functional efficacy with biodistribution data. Although both nontargeted and transferrin-targeted siRNA nanoparticles exhibit similar biodistribution and tumor localization by PET, transferrin-targeted siRNA nanoparticles reduce tumor luciferase activity by {approx}50% relative to nontargeted siRNA nanoparticles 1 d after injection. Compartmental modeling is used to show that the primary advantage of targeted nanoparticles is associated with processes involved in cellular uptake in tumor cells rather than overall tumor localization. Optimization of internalization may therefore be key for the development of effective nanoparticle-based targeted therapeutics.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1978218/PubMed CentralArticle
https://doi.org/10.1073/pnas.0707461104DOIUNSPECIFIED
https://doi.org/10.1073/pnas.0707461104DOIUNSPECIFIED
Additional Information:Copyright © 2007 by the National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Mark E. Davis, August 7, 2007 (sent for review July 5, 2007) We thank Dr. Waldemar Ladno, Dr. David Stout, Judy Edwards, Antonia Luu, and Amanda Armijo for assistance with micro-PET/CT imaging and Calando Pharmaceuticals (Pasadena, CA) for the gift of cyclodextrin-containing polycations, adamantane-PEG, and adamantane-PEG-Tf. This work was supported by a National Science Foundation Graduate Research Fellowship (to D.W.B.) and National Cancer Institute Grant CA119347. Author contributions: D.W.B., H.S., W.A.W., and M.E.D. designed research; D.W.B., H.S., and I.J.H. performed research; D.W.B., H.S., W.A.W., and M.E.D. analyzed data; and D.W.B. wrote the paper. Conflict of interest statement: M.E.D. is a consultant to and has stock in Calando Pharmaceuticals.
Funders:
Funding AgencyGrant Number
NSF Graduate Research FellowshipUNSPECIFIED
National Cancer InstituteCA119347
Subject Keywords:kinetic modeling, multimodality imaging, targeted delivery, tumor uptake
Issue or Number:39
PubMed Central ID:PMC1978218
Record Number:CaltechAUTHORS:BARpnas07
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:BARpnas07
Official Citation:Derek W. Bartlett, Helen Su, Isabel J. Hildebrandt, Wolfgang A. Weber, and Mark E. Davis Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging PNAS 2007 104 (39) 15549-15554; published ahead of print September 17, 2007, doi:10.1073/pnas.0707461104
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8844
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:20 Sep 2007
Last Modified:02 Oct 2019 23:54

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