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Doxorubicin-Loaded Human Serum Albumin Nanoparticles Overcome Transporter-Mediated Drug Resistance in Drug-Adapted Cancer Cells

Onafuye, Hannah, Pieper, Sebastian, Mulac, Dennis, Jr., Jindrich Cinatl, Wass, Mark N., Langer, Klaus, Michaelis, Martin (2019) Doxorubicin-Loaded Human Serum Albumin Nanoparticles Overcome Transporter-Mediated Drug Resistance in Drug-Adapted Cancer Cells. Beilstein Journal of Nanotechnology, 10 . pp. 1707-1715. ISSN 2190-4286. (doi:10.3762/bjnano.10.166)

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Abstract

Resistance to systemic drug therapy is a major reason for the failure of anticancer therapies. Here, we tested doxorubicin-loaded human serum albumin (HSA) nanoparticles in the neuroblastoma cell line UKF-NB-3 and its ABCB1-expressing sublines adapted to vincristine (UKF-NB-3rVCR1) and doxorubicin (UKF-NB-3rDOX20). Doxorubicin-loaded nanoparticles displayed increased anticancer activity in UKF-NB-3rVCR1 and UKF-NB-3rDOX20 cells relative to doxorubicin solution, but not in UKF-NB-3 cells. UKF-NB-3rVCR1 cells were re-sensitised by nanoparticle-encapsulated doxorubicin to the level of UKF-NB-3 cells. UKF-NB-3rDOX20 cells displayed a more pronounced resistance phenotype than UKF-NB-3rVCR1 cells and were not re-sensitised by doxorubicin-loaded nanoparticles to the level of parental cells. ABCB1 inhibition using zosuquidar resulted in similar effects like nanoparticle incorporation, indicating that doxorubicin-loaded nanoparticles successfully circumvent ABCB1-mediated drug efflux. The limited re-sensitisation of UKF-NB-3rDOX20 cells to doxorubicin by circumvention of ABCB1-mediated efflux is probably due to the presence of multiple doxorubicin resistance mechanisms. So far, ABCB1 inhibitors have failed in clinical trials probably because systemic ABCB1 inhibition results in a modified body distribution of its many substrates including drugs, xenobiotics, and other molecules. HSA nanoparticles may provide an alternative, more specific way to overcome transporter-mediated resistance.

Item Type: Article
DOI/Identification number: 10.3762/bjnano.10.166
Uncontrolled keywords: ABCB1; cancer; doxorubicin; drug resistance; human serum albumin; nanoparticles; transporter
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Martin Michaelis
Date Deposited: 04 Sep 2019 09:00 UTC
Last Modified: 05 Sep 2019 11:08 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/76174 (The current URI for this page, for reference purposes)
Wass, Mark N.: https://orcid.org/0000-0001-5428-6479
Michaelis, Martin: https://orcid.org/0000-0002-5710-5888
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