Selective induction of apoptotic cell death in lung carcinoma cells by curcumin-loaded PEGylated lipid nanoparticles with minimal normal tissue toxicity: in vitro and in vivo toxicity evaluation by oral delivery

Abstract

Insufficient drug concentration, systemic toxicity in associated organs and meaningful penetration to the site of action remain major challenges in augmenting the therapeutic efficacy against heterogeneous diseases such as lung cancer, which have become a major burden to society. In this case, oral delivery of smart nanoparticles can offer better patient compliance compared to the intravenous administration routes. Herein, we demonstrate a strategy to produce curcumin-loaded sub-micron sized PEGylated lipid particles (CSLNs) with a controlled size and narrow polydispersity to expand the chemotherapeutic treatment of lung cancer, which could inhibit the migration and invasion of cancer cells. PEGylation improved the stability and bioavailability of curcumin. These CSLNs (10, 20 and 40 μM) were found to induce preferential toxicity in a non-small cell lung cancer cell line (A549) by altering its morphology and induction of apoptosis in a concentration and time-dependent manner compared to normal lung epithelial cells (WI26). The high cytotoxicity of CSLNs was attributed to their higher internalization in the cancer cells (∼2.0–4.5 fold) compared to the normal lung cells. Confocal microscopy revealed the significantly higher accumulation of curcumin (2–4 fold) in the nucleus of the lung cancer cells. Flow cytometry analysis further revealed that the percentage of cells in the sub-G1 phase was significantly higher when treated with CSLNs compared to the bare CUR-treated A549 cells. The in vivo sub-acute toxicity studies indicated that the CSLNs were free from any adverse side effects upon oral administration up to a dose of 200 mg kg⁻¹ day⁻¹ for 28 days. The histopathological analysis and haematological parameters indicated that there was no significant alteration in the cellular mechanism or metabolic activity of the SLN-treated cells. Thus, this rationally designed oral delivery vehicle provides a promising approach for lung cancer therapy with minimum systemic toxicity.