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

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Research

Background:

• Multidrug resistance (MDR) is a major challenge in cancer chemotherapy, primarily mediated by ATP-Binding Cassette (ABC) drug efflux transporters like P-glycoprotein (Pgp).
• Curcumin (CURC) exhibits Pgp inhibitory properties but suffers from poor solubility and bioavailability, limiting its clinical application.

Purpose of the Study:

• To develop and validate biocompatible solid lipid nanoparticles (SLNs) loaded with curcumin (CURC) to enhance its stability, dispersibility, and cellular uptake.
• To evaluate the efficacy and safety of CURC-loaded SLNs, with or without chitosan coating, in overcoming Pgp-mediated chemoresistance in triple-negative breast cancer (TNBC).

Main Methods:

• Curcumin (CURC) was loaded into solid lipid nanoparticles (SLNs), some coated with chitosan.
• The efficacy of CURC-loaded SLNs was assessed by measuring intracellular doxorubicin retention and toxicity in Pgp-expressing TNBC cells.
• The underlying mechanisms, including reactive oxygen species (ROS) levels and the Akt/IKKα-β/NF-kB signaling pathway, were investigated.
• In vivo studies evaluated the rescue of doxorubicin sensitivity in drug-resistant TNBC tumors.

Main Results:

• CURC-loaded SLNs demonstrated a 5-10 fold increase in intracellular doxorubicin retention and toxicity compared to free CURC in TNBC cells.
• The enhanced efficacy was attributed to decreased intracellular ROS, inhibition of the Akt/IKKα-β/NF-kB axis, and reduced Pgp transcriptional activation.
• CURC-loaded SLNs successfully restored doxorubicin sensitivity in resistant TNBC tumors without inducing systemic toxicity.

Conclusions:

• CURC-loaded SLNs represent a promising strategy to enhance the stability and bioavailability of curcumin.
• This novel formulation effectively overcomes Pgp-mediated chemoresistance in TNBC by targeting key intracellular pathways.
• Combination therapy with CURC-loaded SLNs and doxorubicin offers a safe and effective approach to combat chemoresistant TNBC.