title: Dextran-based doxorubicin nanocarriers with improved tumor penetration.
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.
authors: Australian Centre for Nanomedicine and §Biomedical Imaging Facility, Mark Wainwright Analytical Centre, University of New South Wales , Sydney, Australia.
authors: Sharon M
authors: SM
authors: Sagnella
authors: Hien
authors: H
authors: Duong
authors: Alex
authors: A
authors: MacMillan
authors: Cyrille
authors: C
authors: Boyer
authors: Renee
authors: R
authors: Whan
authors: Joshua A
authors: JA
authors: McCarroll
authors: Thomas P
authors: TP
authors: Davis
authors: Maria
authors: M
authors: Kavallaris
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003911:Dextrans / Q000008:administration & dosage* / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage* / Q000378:metabolism; D004337:Drug Carriers / Q000008:administration & dosage* / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects* / Q000502:physiology; D006801:Humans
chemical_list: D000970:Antineoplastic Agents; D003911:Dextrans; D004337:Drug Carriers; D004317:Doxorubicin