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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



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.


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.


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.


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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Drug delivery system


Docosahexaenoic acid


Drug loading




Entrapment efficiency


Enhanced permeability and retention




Nanostructured lipid carrier


Peanut oil


Solid lipid nanoparticles




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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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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).

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  • cancer therapy
  • docosahexaenoic acid
  • doxorubicin
  • nanostructured lipid carrier
  • resistance overcoming