Optimization of cytotoxic properties of magnetic nanoparticle-based doxorubicin delivery system

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Abstract

Doxorubicin (DOX) is a widely used cytotoxic drug with high antitumor activity, but its use is accompanied by side effects. The development of DOX delivery systems that can minimize systemic toxicity and increase therapeutic efficacy is an urgent task in modern oncology. We investigated the process of loading nanoparticles (NPs) with DOX under conditions that promote DOX precipitation in order to achieve maximum sorption efficiency. For this purpose, polymer-stabilized magnetic NPs were synthesized, and the efficiency of loading and precipitation was studied in dependence on the buffer, DOX concentration, and incubation time with the drug. It was shown that in solutions with the most pronounced DOX precipitate formation (phosphate and borate buffers) loading proceeded maximally efficiently. In a phosphate buffer at an initial DOX concentration of 667 μg/mL, the loade was 886 mg DOX/g NPs. The sorption of DOX on NPs under these conditions reached 85% of DOX already within the first hour, and increased to 90% within 3 h. The release of DOX from NPs was 25% at pH 7.4 and 96% at pH 5.4. The survival analysis of EMT-HER2 breast cancer cells showed that the cytotoxicity of NPs loaded with DOX under precipitation conditions was 8 times higher than that of NPs loaded at a concentration of 20 μg/mL, i.e. when DOX does not form a precipitate. This allows us to consider NPs loaded with precipitated DOC as an effective delivery system that, without impairing the cytotoxic properties of the drug, can significantly increase its content and release in tumor cells.

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About the authors

А. I. Kurtova

Moscow Institute of Physics and Technology

Author for correspondence.
Email: viktoriya.shipunova@phystech.edu

Institute of Future Biophysics

Russian Federation, Dolgoprudny, Moscow Region

A. V. Svetlakova

Moscow Institute of Physics and Technology

Email: viktoriya.shipunova@phystech.edu

Institute of Future Biophysics

Russian Federation, Dolgoprudny, Moscow Region

O. А. Kolesnikova

Moscow Institute of Physics and Technology

Email: viktoriya.shipunova@phystech.edu

Institute of Future Biophysics

Russian Federation, Dolgoprudny, Moscow Region

V. O. Shipunova

Moscow Institute of Physics and Technology; Nanobiomedicine Division, Sirius University of Science and Technology

Email: viktoriya.shipunova@phystech.edu

Institute of Future Biophysics

Russian Federation, Dolgoprudny, Moscow Region; Sirius Federal Territory, Krasnodar region

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Supplementary files

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2. Fig. 1. Study design. a – Synthesis and modification of NPs. b – Scheme of experiments to optimize sorption conditions and test NPs with maximum DOC loading. CMD – carboxymethyldextran.

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3. Fig. 2. Characteristics of the obtained magnetic nanoparticles. a, b – Micrographs of unmodified NPs obtained using SEM (a) and TEM (b). c – Histogram of NP size distribution based on the results of processing microelectron photographs. d – Efficiency of DOC sorption on NPs in different buffers. d – Photographs of test tubes after DOC sorption on NPs in different buffers.

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4. Fig. 3. Sorption of DOC on nanoparticles in PBS. a – Dependence of sorption efficiency on the initial concentration of DOC. b – Mass of sorbed DOC at different initial concentrations of DOC. c – Hydrodynamic radius of NPs before sorption and after sorption at different concentrations of DOC. d – Photographs of test tubes after 15 h of sorption of DOC with different initial concentrations on NPs (without treatment in an ultrasonic bath). d – Movement of NPs with DOC sediment (see 3d, [DOC] = 667 μg/ml) to the side wall of the test tube under the action of a magnet. e – Dependence of sorption efficiency on time. g – Efficiency of DOC release from NPs in PBS at pH 7.4 and 5.5.

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5. Fig. 4. Cytotoxicity of NPs after DOC sorption at different concentrations. a – Dependence of cell survival on the concentration of NPs loaded at different initial concentrations of DOC (1–5) and unloaded (6). b – Values ​​of СC50 for NPs loaded at different concentrations of DOC (1–6 from a). c – Dependence of cell survival on the concentration of DOC loaded into NPs at different initial concentrations (1–5) and free DOC. d – Values ​​of СC50 for DOC loaded onto NPs at different concentrations (1–6 from c).

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