Lapatinib-incorporated lipoprotein-like nanoparticles: preparation and a proposed breast cancer-targeting mechanism

Abstract

Aim: Lapatinib is a dual inhibitor of EGFR and human epidermal growth factor receptor 2 (HER2), and used to treat advanced breast cancer. To overcome its poor water solubility, we constructed lapatinib-incorporated lipoprotein-like nanoparticles (LTNPs), and evaluated the particle characteristics and possible anti-breast cancer mechanisms. Methods: LTNPs (lapatinib bound to albumin as a core, and egg yolk lecithin forming a lipid corona) were prepared. The particle characteristics were investigated using transmission electron microscopy (TEM) and atomic force microscopy (AFM). The uptake and subcellular localization of LTNPs, as well as the effects of LTNPs on cell cycle were examined in BT-474 human breast cancer cells in vitro. Mice bearing BT-474 subcutaneous xenograft were intravenously injected with coumarin-6 loaded LTNPs (30 mg/kg) to study the targeting mechanisms in vivo. Results: The LTNPs particles were generally spherical but flexible under TEM and AFM, and approximately 62.1 nm in size with a zeta potential of 22.80 mV. In BT-474 cells, uptake of LTNPs was mediated by endosomes through energy-dependent endocytosis involving clathrin-dependent pinocytosis and macropinocytosis, and they could effectively escape from endosomes to the cytoplasm. Treatment of BT-474 cells with LTNPs (20 μg/mL) induced a significant cell arrest at G 0 /G 1 phase compared with the same concentration of lapatinib suspension. In mice bearing BT-474 xenograft, intravenously injected LTNPs was found to target and accumulate in tumors, and colocalized with HER2 and SPRAC (secreted protein, acidic and rich in cysteine). Conclusion: LTNPs can be taken up into breast cancer cells through specific pathways in vitro, and targeted to breast cancer xenograft in vivo via enhanced permeability and retention effect and SPARC.

Insight into nanoparticle cellular uptake and intracellular targeting

“…Micron size particles are generally known to internalize the cells via macropinocytosis [83], however; most of the literature reports highlight that the nanoparticles undergo cellular internalization via more than one endocytic pathway. Recently, Zhang et al [84] reported lapatinib loaded nanoparticles formulated with a core of albumin and a lipid corona formed by the egg yolk lecithin. The nanoparticles exhibited ~62 nm and a zeta potential of 22.80 mV and were demonstrated to internalize the BT-474 cells through energy-dependent endocytosis involving clathrin-dependent pinocytosis and macropinocytosis.…”

Application of atomic force microscopy in cancer research

“…Lapatinib is poorly soluble in water, but after being encapsulated in lipoproteins to form nanoparticles (LTNPs), its water solubility increases from 7 μg/mL to 10 mg/mL or more. AFM measurements showed that LTNPs are spherical particles, and that the height of the particles is not positively correlated with the diameter, as the diameter is about 60 nm and the height is less than 3 nm [ 118 ].…”

Co-delivery of docetaxel and silibinin using pH-sensitive micelles improves therapy of metastatic breast cancer

“…Currently, chemotherapy is one of the most important treatment strategies for metastatic cancer, but its therapeutic effect is impaired by toxic effects on both cancer cells and normal cells [7,8] . Fortunately, nanodrug delivery systems can break through various biological barriers by taking advantage of the enhanced penetration and retention (EPR) effects of solid tumors [9][10][11][12][13] to increase the intra-tumoral accumulation of drugs, reduce the side effects of chemotherapy [3,[14][15][16][17][18] and potentially inhibit metastatic breast cancer.…”