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Pharmaceutics. 2020 Jan 24;12(2). pii: E96. doi: 10.3390/pharmaceutics12020096.

Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells.

Author information

1
Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy.
2
Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, 33 El Bohouth St., 12622 Dokki, Giza, Egypt.
3
Department of Drug Science and Technology, via P. Giuria 9, 10125 Torino, Italy.
4
Chemistry of Medicinal Plants Department, Biology Unit, Central Laboratory of Pharmaceutical and Drug Industries Research Division, National Research Centre, 33 El Bohouth St., Dokki 12622 , Giza, Egypt.
5
Zoology Department, Faculty of Science, Cairo University, Gamaa Street, Dokki 12622 , Giza, Egypt.

Abstract

Multidrug resistance (MDR) is a critical hindrance to the success of cancer chemotherapy. The main thing responsible for MDR phenotypes are plasma-membranes associated with adenosine triphosphate (ATP) Binding Cassette (ABC) drug efflux transporters, such as the P-glycoprotein (Pgp) transporter that has the broadest spectrum of substrates. Curcumin (CURC) is a Pgp inhibitor, but it is poorly soluble and bioavailable. To overcome these limitations, we validated the efficacy and safety of CURC, loaded in biocompatible solid lipid nanoparticles (SLNs), with or without chitosan coating, with the goal of increasing the stability, homogeneous water dispersibility, and cellular uptake. Both CURC-loaded SLNs were 5-10-fold more effective than free CURC in increasing the intracellular retention and toxicity of doxorubicin in Pgp-expressing triple negative breast cancer (TNBC). The effect was due to the decrease of intracellular reactive oxygen species, consequent inhibition of the Akt/IKKα-β/NF-kB axis, and reduced transcriptional activation of the Pgp promoter by p65/p50 NF-kB. CURC-loaded SLNs also effectively rescued the sensitivity to doxorubicin against drug-resistant TNBC tumors, without signs of systemic toxicity. These results suggest that the combination therapy, based on CURC-loaded SLNs and doxorubicin, is an effective and safe approach to overcome the Pgp-mediated chemoresistance in TNBC.

KEYWORDS:

P-glycoprotein; curcumin; doxorubicin resistance; solid lipid nanoparticles; triple negative breast cancer

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