Journal
BIOMACROMOLECULES
Volume 15, Issue 1, Pages 262-275Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bm401526d
Keywords
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Funding
- Children's Cancer Institute Australia for Medical Research
- Balnaves Foundation
- National Health and Medical Research Council [NHMRC APP1008719]
- Cancer Council New South Wales Program Grant
- Cancer Institute New South Wales Career Development Fellowship
- NHMRC Senior Research Fellowship [658611]
- Australian Postdoctoral Award [ARC-DP1092640]
- Australian Research Council [ARC-FT 120100096]
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Drug delivery systems with improved tumor penetration are valuable assets as anticancer agents. A dextran-based nano carrier 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 similar to 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 similar to 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 mu M. 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.
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