3.2.1. Targeting Folate Receptor

One of the most exploited targeting ligands, folic acid, has been employed to decorate MSN for targeting folate receptor, overexpressed in many tumors compared to healthy tissues [78,79]. The folate receptors are four glycopolypeptide members (FR α, FRβ, FRγ and FRδ), among which the alpha isoform, folate receptor α (FR α) is a glycosylphosphatidylinositol anchored cell surface receptor and has been reported to be overexpressed in solid tumors, such as ovarian, cervical, lung, breast, kidney, colorectal, and brain tumors [80]. In mostly 80–90% of epithelial ovarian cancers, other gynecological cancers, lung cancers and breast cancers, the FR α is highly overexpressed and gaining increasing importance to be exploited for targeted cancer therapy [81]. Considering this fact, several research groups have reported the enhanced specific cellular uptake of MSN in various cancer cells, having overexpressed folate receptors by modifying MSN surface with folic acid [82–86]. Nonetheless, using two di fferent human pancreatic cancer xenografts on di fferent mouse species, Lu et al. have also shown dramatic improvements in tumor-suppression e ffect by using folic acid functionalized camptothecin-loaded MSN in comparison with unfunctionalized MSN [87]. Moreover, along with using folic acid, <sup>L</sup>ópez et al. have decorated MSN with triphenylphosphine (TPP), in order to target tumor cells, as well as the mitochondria of the tumor cells [88]. Conversely, instead of using folic acid, Rosenholm et al. have used methotrexate (MTX) as both a targeting ligand and a cytotoxic agen<sup>t</sup> for cancer therapy, due to its high a ffinity for folate receptors and showed enhanced cancer-cell apoptosis by treating MTX incorporated MSN relative to free MTX [89].

## 3.2.2. Targeting Transferrin Receptor

There are two subtypes of transferrin receptors (TFRs), TFR1 and TFR2, which complexes with iron to facilitate iron metabolism in cells. Hence, the dysregulated expression of any subtype disorders can impair iron metabolism and eventually induce tumorigenesis and cancer progression [90]. It has been reported that TFR1 is abundantly expressed in many cancer types, e.g., liver, breast, lung, pancreatic, and colon cancer cells [90,91], and thus can be exploited as an important target for drug delivery. In order to improve the tumor specific delivery of MSN carrier, transferrin (Tf) which is a ligand of TFR1, has been widely exploited in surface modification of MSN [92]. As evidenced by the available studies targeting TFR1, Tf-modified MSN exhibit enhancement in nanoparticle uptake by Panc-1 cancer cells [93]. Additionally, Montalvo-Quiros et al. have used MSN as nanovehicles decorated with Tf to provide a nanoplatform for the nucleation and immobilization of silver nanoparticles (AgNPs) and demonstrated that only the nanosystem functionalized with Tf can transport the AgNPs inside the human hepatocarcinoma (HepG2) cells overexpressing Tf receptors [94]. Nevertheless, Tf-decorated MSN have been exploited for sorafenib delivery in thyroid cancer therapy [95]. Importantly, the overexpression of TFRs on the brain capillary endothelial cells (BCECs) of the blood-brain barrier (BBB) and glioblastoma multiforme (GBM) provides a route to allow e ffective chemotherapeutic penetration to the site of brain tumor [96]. Herein, few research groups have developed Tf-conjugated MSN to deliver the chemotherapeutics to glioma cells across the BBB [97,98].

## 3.2.3. Targeting Integrin Receptor and Nuclear Targeting

Integrin receptors, the α/β heterodimeric transmembrane glycoproteins, are overexpressed on angiogenetic endothelial cells and certain tumor cells, whereas they are absent (or present in basal levels) in pre-existing endothelial cells and normal tissues [19,99]. This makes integrins, especially αvβ3 integrin receptors, a promising target in cancer therapy and RGD (arginine-glycine-aspartic acid) based peptides have found widespread exploitations for targeting chemotherapeutics to both tumor and tumor vasculatures via the overexpressed integrin receptors [100]. Therefore, peptides including the RGD motif have been widely used in surface decoration of MSN for targeted cancer therapy [101–106]. Moreover, Pan et al. have shown the in vivo efficacy of doxorubicin-loaded MSN grafted with RGD-motif. The same research group has further determined better tumor accumulation and reduced tumor size by coupling cell-penetrating and nuclear-targeting TAT peptide to the MSN along with RGD. Additionally, side e ffects of bare MSN to accumulate in liver and spleen have been distinctly minimized by treating RGD/TAT-MSN [107].

## 3.2.4. Targeting EGF Receptor and HER2 Receptor

Epidermal growth factor receptor (EGFR or ErbB1), a tyrosine kinase receptor, is a key factor in epithelial malignancies, in terms of enhancing tumor growth, invasion, and metastasis [108]. Overexpression of EGFR has been widely observed in many cancers including lung (especially non-small-cell lung carcinoma), colon, ovary, head and neck and breast cancers [109]. As EGFR has emerged as an attractive target for anti-lung cancer drug research, its ligand or antibody has been extensively employed in capping moiety for the active targeting of MSN in lung cancer cells. For example, She et al. have used amine functionalized MSN to conjugate with EGFs (epidermal growth factors) for targeting EGFR positive cells [110]. Sundarraj et al. have shown elevated accumulation of EGFR-MSN-cisplatin drug delivery system in EGFR overexpressed lung adenocarcinoma cells (A549) than that in normal lung cells (L-132). They have also used the non-small cell lung cancer nude mice model to determine the increased and prolonged cisplatin intratumoral distribution and enhanced tumor-cell apoptosis by treating EGFR-MSN-cisplatin [111]. On the other hand, Wang et al. have used cetuximab, a monoclonal antibody of EGFR as a capping agen<sup>t</sup> of MSN loaded with anti-cancer drugs including doxorubicin and gefitinib, to specifically target lung cancer cells exploiting EGFR overexpression [112].

In addition to the EGFR, human epidermal growth factor receptor 2 (HER2)/ErbB2 is another member of the ErbB family of type-1 tyrosine kinases and a proto-oncogene, with a vast role of ErbB receptors in malignant transformation [113]. The overexpression of HER2 receptor in breast cancer alongside lungs, ovary and gastric/gastroesophageal cancers plays a major role in the angiogenic process and makes HER2 an important target in cancer therapy [114]. Furthermore, it has been reported that HER2 specific antibodies or antibody-fragments (e.g., trastuzumab) have been used in the surface modification of MSN for the selective targeting of breast cancer cells [115].
