Development of targeted lipid nanoparticles for the combined therapy of triple negative breast cancer: can curcumin and 6-aminoflavone promote doxorubicin in vitro efficacy?

In the study of triple-negative breast cancer (TNBC) therapeutic approaches, researchers have recently focused on exploiting P-glycoprotein (P-gp) and hypoxia-inducible factor (HIF) inhibitors to enhance the effectiveness of chemotherapeutic agents, which are often limited by poor specificity and high toxicity. Additionally, herbal medicines have shown promising results as non-toxic P-gp and HIF inhibitors. However, the co-administration of chemotherapeutic agents with natural P-gp inhibitors, such as curcumin (CUR) or HIF-inhibitors like 6-aminoflavon (AF), remains challenging due to pharmacokinetic constraints. In the present work, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are employed as drug delivery systems.

Highlights

• TNBC therapy is limited by multidrug resistance of neoplastic cells due to the expression of P-glycoprotein.
• A strategy: to load antitumor drug into NPs and co-administer P-gp and HIF inhibitors.
• Development of C₁₂-DOXO, CUR, and AF-loaded SLNs: a strategy to flexibly modulate the dose of each compounds.
• Positive results in cell viability and drug uptake on human DOXO-sensitive/resistant TNBC cell lines were evidenced when the C₁₂-DOXO and CUR or AF in HA-decorated SLN were co-administered.

CUR, AF, and a lipophilic doxorubicin (DOXO) ester (C₁₂-DOXO) were individually loaded into both systems and subsequently co-formulated. SLNs, both naked and hyaluronic acid (HA)-decorated, and NLCs were prepared and characterized. Given that NLCs have not yielded fully satisfactory results regarding drug entrapment and recovery, we have, for the time being, focused further characterization studies and cell line experiments exclusively on SLNs. SLNs were therefore tested on DOXO-sensitive and DOXO-resistant TNBC cell lines (MDA-MB-231 and MDA-MB-231/DX cells, respectively).

HA-decorated SLNs showed effective C₁₂-DOXO accumulation in P-gp-expressing cells, significantly reducing cell viability, including in DOXO-resistant cells. The combination of HA-decorated SLNs containing C₁₂-DOXO (SLN-C₁₂-DOXO-HA) with HA-decorated SLNs containing CUR (SLN-CUR-HA) or AF (SLN-AF-HA) demonstrated a significant reduction in cell viability across all concentrations, exceeding the cytotoxicity noted in the application of SLN-C₁₂-DOXO-HA alone, especially at higher concentrations in both DOXO sensitive and resistant cell lines.

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Materials

HA 1600 kDa, sweet almond oil (virgin, Eur. Ph.), grape seed oil (refined), olive oil (virgin, Eur. Ph.) and Compritol® 888 ATO (glyceryl dibehenate) were purchased from Farmalabor (Barletta, Italy), cetyltrimethylammonium bromide (CTAB), ethyl acetate (EA, purity ≥ 99.5%), propylene glycol (PG, purity ≥ 99.5%), myristic acid (purity ≥ 98.5%), AF, CUR, sesame oil (refined), dimethyl sulfoxide (DMSO, purity ≥ 99.9%) and Tween®80 were purchased from Merck (Darmstadt, Germany), Epikuron®200 (phosphatidylcholine 92%) was from Cargill (Minneapolis, MN, USA), DOXO was purchased from APAC Pharmaceutical (Columbia, MD, USA), Cremophor®RH60 (PEG-60 hydrogenated castor oil) from BASF (Ludwigshafen am Rhein, Germany) and trilaurin (TL, 98% min.) from Alfa-Aesar (Ward Hill, MA, USA). Deionized water was obtained by a MilliQ water purification system (Millipore, Bedford, MA, USA). Unless specified otherwise, all reagents were purchased from Merck and all solvents were HPLC gradient grade.

Elena Peira, Simona Sapino, Daniela Chirio, Giulia Chindamo, Chiara Riganti, Martina Godel, Konstantin Chegaev, Marina Gallarate, Development of targeted lipid nanoparticles for the combined therapy of triple negative breast cancer: can curcumin and 6-aminoflavone promote doxorubicin in vitro efficacy?, Journal of Drug Delivery Science and Technology, 2024, 106414, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2024.106414.

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