Synthesis of lactoferrin mesoporous silica nanoparticles for pemetrexed/ellagic acid synergistic breast cancer therapy

Despite the clinical approval of few nanomedicines for cancer therapy, some drawbacks still impede their improved efficiency including low drug loading, off-target toxicity and development of multi-drug resistance. Herein, lactoferrin (Lf)-coupled mesoporous silica nanoparticles (MSNPs) were developed for combined delivery of the cytotoxic drug pemetrexed (PMT) and the phytomedicine ellagic acid (EA) for synergistic breast cancer therapy. While the hydrophobic EA was physically encapsulated within the pores of MSNPs via the adsorptive properties of MSNPs and the electrostatic interactions between the negatively charged EA and positively charged amino modified MSNs, the highly water soluble PMT was chemically anchored to the Lf shell through chemical conjugation to the surface of lactoferrin coated MSNPs by carbodiimide reaction to avoid pre-mature drug release and systemic toxicity. The dual drug-loaded Lf-MSNPs (284 nm) demonstrated a sequential faster release of EA followed by a sustained release of PMT. The dual drug-loaded Lf-MSNPs exhibited highest cytotoxicity against MCF-7 (Michigan Cancer Foundation-7) breast cancer cells as revealed by the lowest combination index (CI= 0.885) compared to free drugs. The combination index value (< 1) revealed synergy between both loaded drugs. Furthermore, high cellular uptake of the nanocarriers into MCF-7 breast cancer cells was observed via Lf-receptor mediated endocytosis. Altogether, the dual drug-loaded Lf-targeted MSNPs showed to be a promising carrier for breast cancer therapy through triggering different signaling pathways, and hence overcoming the multi-drug resistance and minimizing the systemic toxicity.