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Novel Nanostructured Lipid Carrier Co-Loaded with Doxorubicin and Docosahexaenoic Acid Demonstrates Enhanced in Vitro Activity and Overcomes Drug Resistance in MCF-7/Adr Cells

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ABSTRACT

Purpose

To develop a nanostructured lipid carrier (NLC) co-loaded with doxorubicin and docosahexaenoic acid (DHA) and to evaluate its potential to overcome drug resistance and to increase antitumoral effect in MCF-7/Adr cancer cell line.

Methods

The NLC was prepared by a hot homogenization method and characterized for size, zeta potential, entrapment efficiency (EE) and drug loading (DL). Drug release was evaluated by dialysis in complete DMEM, and NLC aggregation was assayed in the presence of serum. The cytotoxicity of formulations, doxorubicin uptake or penetration were evaluated in MCF-7 and MCF-7/Adr as monolayer or spheroid models.

Results

The formulation had a size of about 80 nm, negative zeta potential, EE of 99%, DL of 31 mg/g, a controlled drug release in DMEM and no particles aggregation in presence of serum. The NLC loaded with doxorubicin and DHA showed the same activity as free drugs against MCF-7 but a stronger activity against MCF-7/Adr cells. In monolayer model, the doxorubicin uptake as free and encapsulated form was similar in MCF-7 but higher for the encapsulated drug in MCF-7/Adr, suggesting a bypassing of P-glycoprotein bomb efflux. For spheroids, the NLC loaded with doxorubicin and DHA showed a prominent cytotoxicity and a greater penetration of doxorubicin.

Conclusions

These findings suggest that the co-encapsulation of doxorubicin and DHA in NLC enhances the cytotoxicity and overcomes the doxorubicin resistance in MCF-7/Adr.

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Abbreviations

DDS:

Drug delivery system

DHA:

Docosahexaenoic acid

DL:

Drug loading

DOX:

Doxorubicin

EE:

Entrapment efficiency

EPR:

Enhanced permeability and retention

NE:

Nanoemulsion

NLC:

Nanostructured lipid carrier

PO:

Peanut oil

SLN:

Solid lipid nanoparticles

TEA:

Triethanolamine

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported by “Minas Gerais State Agency for Research and Development” (FAPEMIG, Brazil) and by the Brazilian agencies. The authors wish to kindly thank Dr. William Hartner for his helpful advice in editing this manuscript. The authors state no conflict of interest and have received no payment in preparation of this manuscript. All authors have approved the final article.

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Authors and Affiliations

  1. Department of Pharmaceutics, Faculty of Pharmacy, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil

    Samuel V. Mussi, Mônica C. Oliveira & Lucas A. M. Ferreira

  2. Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, Massachusetts, USA

    Samuel V. Mussi, Rupa Sawant, Federico Perche & Vladimir P. Torchilin

  3. Department of Genetic and Morphology, Biological Sciences Institute, Brasília University, Brasília, DF, Brazil

    Ricardo B. Azevedo

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  1. Samuel V. Mussi
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  2. Rupa Sawant
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  3. Federico Perche
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  4. Mônica C. Oliveira
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  5. Ricardo B. Azevedo
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  6. Lucas A. M. Ferreira
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  7. Vladimir P. Torchilin
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Correspondence to Vladimir P. Torchilin.

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Mussi, S.V., Sawant, R., Perche, F. et al. Novel Nanostructured Lipid Carrier Co-Loaded with Doxorubicin and Docosahexaenoic Acid Demonstrates Enhanced in Vitro Activity and Overcomes Drug Resistance in MCF-7/Adr Cells. Pharm Res 31, 1882–1892 (2014). https://doi.org/10.1007/s11095-013-1290-2

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  • DOI: https://doi.org/10.1007/s11095-013-1290-2

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