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Incorporation of doxorubicin in different polymer nanoparticles and their anticancer activity

Pieper, Sebastian, Onafuye, Hannah, Mulac, Dennis, Cinatl Jr., Jindrich, Wass, Mark N., Michaelis, Martin, Langer, Klaus (2019) Incorporation of doxorubicin in different polymer nanoparticles and their anticancer activity. Beilstein Journal of Nanotechnology, 10 . pp. 2062-2072. ISSN 2190-4286. (doi:10.3762/bjnano.10.201) (KAR id:79499)

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https://dx.doi.org/10.3762/bjnano.10.201

Abstract

Background: Nanoparticles are under investigation as carrier systems for anticancer drugs. The expression of efflux transporters such as the ATP-binding cassette (ABC) transporter ABCB1 is an important resistance mechanism in therapy-refractory cancer cells. Drug encapsulation into nanoparticles has been shown to bypass efflux-mediated drug resistance, but there are also conflicting results. To investigate whether easy-to-prepare nanoparticles made of well-tolerated polymers may circumvent transporter-mediated drug efflux, we prepared poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), and PEGylated PLGA (PLGA-PEG) nanoparticles loaded with the ABCB1 substrate doxorubicin by solvent displacement and emulsion diffusion approaches and assessed their anticancer efficiency in neuroblastoma cells, including ABCB1-expressing cell lines, in comparison to doxorubicin solution.

Results: The resulting nanoparticles covered a size range between 73 and 246 nm. PLGA-PEG nanoparticle preparation by solvent displacement led to the smallest nanoparticles. In PLGA nanoparticles, the drug load could be optimised using solvent displacement at pH 7 reaching 53 µg doxorubicin/mg nanoparticle. These PLGA nanoparticles displayed sustained doxorubicin release kinetics compared to the more burst-like kinetics of the other preparations. In neuroblastoma cells, doxorubicin-loaded PLGA-PEG nanoparticles (presumably due to their small size) and PLGA nanoparticles prepared by solvent displacement at pH 7 (presumably due to their high drug load and superior drug release kinetics) exerted the strongest anticancer effects. However, nanoparticle-encapsulated doxorubicin did not display increased efficacy in ABCB1-expressing cells relative to doxorubicin solution.

Conclusion: Doxorubicin-loaded nanoparticles made by different methods from different materials displayed substantial discrepancies in their anticancer activity at the cellular level. Optimised preparation methods resulted in PLGA nanoparticles characterised by increased drug load, controlled drug release, and high anticancer efficacy. The design of drug-loaded nanoparticles with optimised anticancer activity at the cellular level is an important step in the development of improved nanoparticle preparations for anticancer therapy. Further research is required to understand under which circumstances nanoparticles can be used to overcome efflux-mediated resistance in cancer cells.

Item Type: Article
DOI/Identification number: 10.3762/bjnano.10.201
Uncontrolled keywords: cancer; doxorubicin; drug release; nanoparticles; poly(lactic-co-glycolic acid) (PLGA)
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Martin Michaelis
Date Deposited: 07 Jan 2020 09:54 UTC
Last Modified: 08 Jan 2020 09:20 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/79499 (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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