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Increased brain uptake of targeted nanoparticles by adding an acid-cleavable linkage between transferrin and the nanoparticle core

Clark, Andrew J. and Davis, Mark E. (2015) Increased brain uptake of targeted nanoparticles by adding an acid-cleavable linkage between transferrin and the nanoparticle core. Proceedings of the National Academy of Sciences, 112 (40). pp. 12486-12491. ISSN 0027-8424. PMCID PMC4603510. doi:10.1073/pnas.1517048112. https://resolver.caltech.edu/CaltechAUTHORS:20150922-110528268

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Abstract

Most therapeutic agents are excluded from entering the central nervous system by the blood–brain barrier (BBB). Receptor mediated transcytosis (RMT) is a common mechanism used by proteins, including transferrin (Tf), to traverse the BBB. Here, we prepared Tf-containing, 80-nm gold nanoparticles with an acid-cleavable linkage between the Tf and the nanoparticle core to facilitate nanoparticle RMT across the BBB. These nanoparticles are designed to bind to Tf receptors (TfRs) with high avidity on the blood side of the BBB, but separate from their multidentate Tf–TfR interactions upon acidification during the transcytosis process to allow release of the nanoparticle into the brain. These targeted nanoparticles show increased ability to cross an in vitro model of the BBB and, most important, enter the brain parenchyma of mice in greater amounts in vivo after systemic administration compared with similar high-avidity nanoparticles containing noncleavable Tf. In addition, we investigated this design with nanoparticles containing high-affinity antibodies (Abs) to TfR. With the Abs, the addition of the acid-cleavable linkage provided no improvement to in vivo brain uptake for Ab-containing nanoparticles, and overall brain uptake was decreased for all Ab-containing nanoparticles compared with Tf-containing ones. These results are consistent with recent reports of high-affinity anti-TfR Abs trafficking to the lysosome within BBB endothelium. In contrast, high-avidity, Tf-containing nanoparticles with the acid-cleavable linkage avoid major endothelium retention by shedding surface Tf during their transcytosis.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1517048112 DOIArticle
http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1517048112/-/DCSupplementalPublisherSupporting Information
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603510/PubMed CentralArticle
ORCID:
AuthorORCID
Davis, Mark E.0000-0001-8294-1477
Additional Information:© 2015 National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Mark E. Davis, August 27, 2015 (sent for review August 13, 2015). Published ahead of print September 21, 2015. We thank Nathan Dalleska (Caltech Environmental Analysis Center) for his assistance with ICP-MS measurements and Mona Shahgohli (Caltech) for assistance with MALDI-TOF measurements. This work was supported by National Institutes of Health Grant R01 NS0711121 and National Cancer Institute Grant CA 151819. Author contributions: A.J.C. and M.E.D. designed research; A.J.C. performed research; A.J.C. contributed new reagents/analytic tools; A.J.C. and M.E.D. analyzed data; and A.J.C. and M.E.D. wrote the paper. The authors declare no conflict of interest. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1517048112/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
NIHR01 NS0711121
NIHCA 151819
National Cancer InstituteUNSPECIFIED
Subject Keywords:blood–brain barrier; transcytosis; therapeutic delivery; systemic administration; in vivo
Issue or Number:40
PubMed Central ID:PMC4603510
DOI:10.1073/pnas.1517048112
Record Number:CaltechAUTHORS:20150922-110528268
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150922-110528268
Official Citation:Andrew J. Clark and Mark E. Davis Increased brain uptake of targeted nanoparticles by adding an acid-cleavable linkage between transferrin and the nanoparticle core PNAS 2015 112 (40) 12486-12491; published ahead of print September 21, 2015, doi:10.1073/pnas.1517048112
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:60410
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:22 Sep 2015 18:30
Last Modified:10 Nov 2021 22:33

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