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Dextran-based doxorubicin nanocarriers with improved tumor penetration
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Sagnella, Sharon M., Duong, Hien, MacMillan, Alex, Boyer, Cyrille, Whan, Renee, McCarroll, Joshua A., Davis, Thomas P. and Kavallaris, Maria (2014) Dextran-based doxorubicin nanocarriers with improved tumor penetration. Biomacromolecules, Volume 15 (Number 1). pp. 262-275. doi:10.1021/bm401526d ISSN 1525-7797.
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Official URL: http://dx.doi.org/10.1021/bm401526d
Abstract
Drug delivery systems with improved tumor penetration are valuable assets as anticancer agents. A dextran-based nanocarrier system with aldehyde functionalities capable of forming an acid labile linkage with the chemotherapy drug doxorubicin was developed. Aldehyde dextran nanocarriers (ald-dex-dox) demonstrated efficacy as delivery vehicles with an IC50 of 300 nM against two-dimensional (2D) SK-N-BE(2) monolayers. Confocal imaging showed that the ald-dex-dox nanocarriers were rapidly internalized by SK-N-BE(2) cells. Fluorescence lifetime imaging microscopy (FLIM) analysis indicated that ald-dex-dox particles were internalized as intact complexes with the majority of the doxorubicin released from the particle four hours post uptake. Accumulation of the ald-dex-dox particles was significantly enhanced by 30% in the absence of glucose indicating a role for glucose and its receptors in their endocytosis. However, inhibition of clathrin dependent and independent endocytosis and macropinocytosis as well as membrane cholesterol depletion had no effect on ald-dex-dox particle accumulation. In three-dimensional (3D) SK-N-BE(2) tumor spheroids, which more closely resemble a solid tumor, the ald-dex-dox nanoparticles showed a significant improvement in efficacy over free doxorubicin, as evidenced by decreased spheroid outgrowth. Drug penetration studies in 3D demonstrated the ability of the ald-dex-dox nanocarriers to fully penetrate into a SK-N-BE(2) tumor spheroids, while doxorubicin only penetrates to a maximum distance of 50 μM. The ald-dex-dox nanocarriers represent a promising therapeutic delivery system for the treatment of solid tumors due to their unique enhanced penetration ability combined with their improved efficacy over the parent drug in 3D.
Item Type: | Journal Article | ||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||
Journal or Publication Title: | Biomacromolecules | ||||
Publisher: | American Chemical Society | ||||
ISSN: | 1525-7797 | ||||
Official Date: | 2014 | ||||
Dates: |
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Volume: | Volume 15 | ||||
Number: | Number 1 | ||||
Page Range: | pp. 262-275 | ||||
DOI: | 10.1021/bm401526d | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access |
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