# Targeted Lipid-Based Drug Delivery Systems for Lung Cancer Therapy
## 4 Surface Modification
### Ligands Used for NLCs Surface Modification  
As for the NLCs and their functionalisation, many ligands have been attached on their surface to achieve active targeting (Table 2). The Biotin receptor is widely overexpressed in cancer cells, including those of lung cancer. [PERSON] et al. used Biotin as a targeting moiety conjugated with stearylamine on the surface of NLCs which were carrying sunitinib, a tyrosine kinase inhibitor with antitumor activity [88]. When tested on the A549 cell line, the Biotin-modified NLCs showed enhanced cellular uptake in comparison to the free drug and the non-targeted NLCs. The cytotoxicity of the targeted NLCs was higher as well [88]. [PERSON] et al. explored another interesting aspect of functionalisation: the difference between pre- and post-decoration is that the pre-decoration carriers are developed with drugs that have targeting moieties and post-decoration carriers are the ones in which preparation of the carriers occurs first, followed by surface modification. Based on the results, they found out that post-decoration was preferable, as it offered better antitumor activity [141].  
Another study was performed by [PERSON] et al. who investigated the LHRH and its possible effect following surface modification [136]. LHRH can successfully target extracellular receptors which are overexpressed in lung cancer cells. The LHRH-modified NLCs had increased cytotoxicity and allowed the delivery of paclitaxel directly to the tumours. This study achieved dual, active and passive targeting [136]. LHRH was also used by [PERSON] et al. who found that paclitaxel or doxorubicin with siRNA were successfully delivered to the target. The results also showed that the healthy organs and cells were not affected compared to intravenous injection of the investigated drugs [130]. Two ligands, transferrin and hyaluronic acid, had successfully modified the NLCs surface that delivered plasmid DNA (pDNA) to the A549 cell line. The results showed that the combination of these two ligands improved the ability for targeting the cancer cells and decreased systemic cytotoxicity, making them a safe alternative in cancer therapy [142]. Transferrin was also investigated as a single ligand by [PERSON] et al. [89]. Transferrin-decorated NLCs had successfully increased transfection efficiency and increased antitumor activity [89].  
Dual delivery of paclitaxel and 5-demethylmobiletin via cetuximab-modified NLCs has been investigated by [PERSON] et al. [143]. Cetuximab is an antibody which can be used to target EGFR and it has also been approved for colorectal cancer. Sustained release was achieved while cellular uptake by A549 was increased for the targeted NLCs. The delivery of both drugs exhibited decreased cell viability compared to single-drug NLCs and also showed excellent antitumor activity while inhibiting cell proliferation [143]. Lastly, another study which explored the efficiency of dual delivery was performed by [PERSON] et al. where N-Acetyl-D-glucosamine was used as a targeting ligand to target glucose receptors which were overexpressed in cancer cells due to hypoxic conditions. The combined targeted NLCs showed better cellular uptake in the A549 cell line than the free drugs [144].