Abstract
A micelle system modified with α-Conotoxin ImI (ImI), a potently antagonist for alpha7 nicotinic acetylcholine receptor (α7-nAChR) previously utilized for targeting breast cancer, was constructed. Its targeting efficiency and cytotoxicity against non-small cell lung cancer (NSCLC) highly expressing α7-nAChR was investigated. A549, a non-small cell lung cancer cell line, was selected as the cell model. The cellular uptake study showed that the optimal modification ratio of ImI on micelle surface was 5% and ImI-modification increased intracellular delivery efficiency to A549 cells via receptor-mediated endocytosis. Intracellular Ca2+ transient assay demonstrated that ImI modification led to enhanced molecular interaction between nanocarriers and A549 cells. The in vivo near-infrared fluorescence imaging further revealed that ImI-modified micelles could facilitate the drug accumulation in tumor sites compared with non-modified micelles via α7-nAChR mediation. Moreover, docetaxel (DTX) was loaded in ImI-modified nanomedicines to evaluate its in vitro cytotoxicity. As a result, DTX-loaded ImI-PMs exhibited greater anti-proliferation effect on A549 cells compared with non-modified micelles. Generally, our study proved that ImI-modified micelles had targeting ability to NSCLC in addition to breast cancer and it may provide a promising strategy to deliver drugs to NSCLC overexpressing α7-nAChR.
Highlights
Lung cancer, the most frequently diagnosed cancer, is the leading cause of cancer-related mortality among males and the second leading cause of cancer death among females worldwide (Torre et al, 2015, 2016)
Based on all of the above, our work aims to investigate the targeting potential of ImI-modified nanomedicines for the treatment of a7-nicotinic acetylcholine receptors (nAChRs)-overexpressed non-small cell lung cancer (NSCLC) in vitro and in vivo
Compared with the UV spectrum of NHS-PEG-DSPE, ImI displayed strong absorption peaks near 284 nm, and similar absorption peaks were observed in the UV spectrum of Receptor expression of a7-nAChR on A549 cells
Summary
The most frequently diagnosed cancer, is the leading cause of cancer-related mortality among males and the second leading cause of cancer death among females worldwide (Torre et al, 2015, 2016). It has been largely demonstrated that among different subtypes of nAChRs, the homomeric pentamer a7-nAChR, composed of five a7-subunits symmetrically arranged around a central ion pore, are responsible for cell growth and tumor progression as well as cell death in NSCLC (Cesario et al, 2012; Zhang et al, 2016). It mediates the proliferative, pro-angiogenic, and pro-metastatic activities of nicotine in human NSCLC (Singh et al, 2011; Schuller, 2012). Data from several laboratories have shown that the a7-nAChR antagonists could be considered as potential anticancer agents (Trombino et al, 2004; Russo et al, 2006; Grozio et al, 2008; Paleari et al, 2008a,b), since antagonists (e.g. D-tubocurarine or snake’s long neurotoxin) have an inhibitory effect on tumor growth by binding to a7nAChR (Cesario et al, 2004; Grozio et al, 2007; Catassi et al, 2008; Grozio et al, 2008; Paleari et al, 2008a,b)
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