3.2.5. Targeting VEGF Receptor

The vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) play a critical role in tumor angiogenesis and metastasis. Among the three receptors (VEGFR1, VEGFR2, VEGFR3), VEGFR2 is widely explored as a direct stimulator of angiogenesis [116]. In addition to its constitutive expression on angiogenic endothelial cells, VEGFR2 is found to be overexpressed on several cancer cells such as breast cancer, lung cancer, pancreatic cancer, glioblastoma, gastrointestinal cancer, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, bladder cancer, and osteosarcoma cells [117]. To target VEGFR2, Weibo and co-workers have used VEGF121, a natural VEGFR ligand which has a high binding affinity for VEGFR2 and observed a strong, specific binding of the MSN surface coated with VEGF121 in HUVEC (VEGFR+), but not in 4T1 cells (VEGFR−) [118]. The same group has also demonstrated delivery of the MSN encapsulating the anti-cancer drug, sunitinib in a significantly higher amount to the U87MG tumor by targeting VEGFR exploiting VEGF121 ligand in comparison with the non-targeted delivery [119]. Moreover, Zhang et al. have shown increased targeting ability and retention time of anti-VEGFR2 targeted MSN in anaplastic thyroid cancer tumor-bearing mouse [120]. Bevacizumab or related antibodies have been also exploited for targeting VEGF receptors.

## 3.2.6. Targeting Mannose Receptor and C-Type Lectin Receptor

Tumor-associated macrophages (TAMs) that exist in the tumor microenvironment promote tumor immunosuppression, angiogenesis, metastasis, and relapse. TAMs expressing the multi-ligand endocytic receptor mannose receptor (CD206/MRC1) have been suggested as a promising therapeutic target for cancer therapy [121]. It has been reported that MSN coupled with mannosylated polyethylenimine (MP) can target macrophage cells and enhance transfection e fficiency through receptor-mediated endocytosis via mannose receptors [122]. Moreover, the C-type lectin receptor is also expressed exclusively by macrophages and exploited for cancer treatment. Lectin-functionalized MSN have recently been experimented in a mouse colon cancer model [123].

## 3.2.7. Other Active Targeted Delivery

There are several other receptors that have also been exploited for targeted delivery using surface-modified MSN. The overexpression of the insulin-like growth factor (IGF) receptor in ovarian cancer has been employed for the e fficient targeted delivery of doxorubicin entrapped in surface modified MSN [124]. Quan et al. have developed lactosaminated MSN (Lac-MSN) for asialoglycoprotein receptor (ASGPR) targeted anticancer drug delivery and showed the e ffectively inhibited growth of HepG2 and SMMC7721 cells by treatment with docetaxel (DTX) loaded in Lac-MSN [125]. The surface of the MSN has also been functionalized with the ligands of somatostatin receptors [126] and also with hyaluronic acid to target CD44 receptors [127]. Furthermore, Chen et al. have shown the significantly larger tumor uptake of vasculature targeting anti-CD105 antibody (TRC105) conjugated MSN, compared to untargeted nanoparticles in a murine breast cancer model [128]. The same group has employed a TRC105 antibody fragment (Fab) for the surface modification of MSN to target tumor vasculature [129]. Besides, Sweeney et al. have attached a bladder-cancer specific peptide named Cyc6 to MSN for active targeting [130]. Apart from small molecules, peptides and antibodies, the synthetic single-stranded DNA or RNA oligonucleotides (aptamers) have been used to decorate MSN for targeting cancer cells [131,132]. Moreover, Nguyen et al. have shown the Toll-like receptor 9 mediated delivery of mesoporous silica cancer vaccine (antigen) to the dendritic cells (the body's most professional antigen presenting cells) [133].

## **4. Stimuli-Responsive Drug Delivery Using MSN**

Although vast efforts have been devoted to active targeting therapy using MSN, the delivery efficacy still needs to be strengthened. During the blood circulation and penetration into the tumor matrix, anticancer drugs may leak from mesopores of MSN, leading to insufficient drug concentration at the tumor site. To overcome this obstacle, "smart" MSNs-modified with environment-responsive gatekeepers were designed. As the characteristics of tumor microenvironment differ from that of normal tissues (e.g., acidic pH, high concentration of glutathione, etc.), MSN can be modified introducing the moiety sensitive to the tumor microenvironment and release the cargo specifically at the tumor site [134,135]. There are internal and external stimuli that have been exploited for the controlled drug release (Figure 2). In this part of the review, we will discuss the pH, redox and enzyme internal stimuli responsive gatekeepers and also the magnetic, light and ultrasound external stimuli responsive gatekeepers frequently used to prepare stimuli responsive MSN.

**Figure 2.** Most relevant stimuli responsive gatekeepers to decorate MSN for controlled cargo release in the cancer site.
