Article Text
PDF
Abstract
Introduction Lung cancer is the leading cause of cancer death worldwide, with an average 5 yr survival rate of just 9.5% in the UK. The success of current chemotherapy regimens for non-small cell lung cancer (NSCLC), the predominant subtype of lung cancer, is hindered by poor tumour penetration and accumulation, and systemic side effects which significantly affect patient quality of life. The field of cancer nanomedicine seeks to overcome these problems by utilising the unique physicochemical properties of nanoparticles; gold-based nanomedicines (AuNPs) show particular promise as they may be able to offer multimodal therapeutics and diagnostics in a single formulation.
Objectives This study aimed to conjugate cisplatin and pemetrexed, a first line therapy for NSCLC, to AuNPs, and investigate their efficacy on tumour cell proliferation compared to free drug. Furthermore, we investigated whether conjugation to AuNPs abrogated the inflammatory and toxic effects of these drugs on non-cancer human pulmonary epithelial cells.
Methods Cisplatin and pemetrexed were conjugated to AuNPs using heterobifunctional polyethylene glycol (PEG) linkers and were characterised by electron microscopy, ICP-OES, dynamic light scattering and thermogravimetric analysis. The effect of conjugates in in vitro cancer (H226 and A549 cells) and non-cancer (human alveolar type I epithelial cells) cell models were measured by electric cell-substrate impedance sensing (ECIS), MTT assay, ELISA and confocal microscopy.
Results Nanoparticle characterisation confirmed successful conjugation of cisplatin and pemetrexed to AuNPs. Confocal microscopy demonstrated that nanoparticles were internalised by cancer cells and distributed throughout the cytoplasm. Further studies showed that conjugates inhibited cancer cell proliferation significantly more than the respective free drug (Figure 1) and abrogated free drug cytotoxicity in non-cancer alveolar type I epithelial cells (0% cell death vs 30% respectively; 10 µM cisplatin; P < 0.001). Conjugates also attenuated chemotherapy-induced IL-6 release in both cancer and non-cancer cells; 10 µM cisplatin induced 6.6-fold and 7-fold greater IL-6 release compared to equimolar conjugates in H226 and alveolar type I epithelial cells respectively ( P < 0.001).
Effect of free drug and AuNP conjugates on cancer cell proliferation. A549 cells were exposed to 10 mM cisplatin (A) or pemetrexed (B) and equimolar concentrations of 20 nm and 40 nm conjugates. Proliferation was measured at 48 hours by electrical cell-substrate impedance. Data expressed as mean ± SE (n = 3). *P < 0.05 conjugate vs free cisplatin, ***P < 0.0001 conjugate vs free pemetrexed
Conclusions We have synthesised gold-based nanomedicines that are more efficacious and biocompatible than free drug in in vitro cell models, suggesting these formulations could have enhanced therapeutic potency and improve patient quality of life.