Zheng Weibin 1, Zhang Boya 1, Yin Xiaochen 1, 2, Wang Xin1, Zhao Qinjian 1
The authors are: 1. 361102 Xiamen, National Center of infectious disease diagnostic reagents and vaccine engineering technology, Xiamen University, State Key Laboratory of molecular vaccinology and molecular diagnostics, School of public health, Xiamen University; 2. 361102 Xiamen, School of life sciences, Xiamen University
Fund Project: National Natural Science Foundation of China (31670939)
[Abstract] in recent years, cancer treatment has been paid more and more attention. Silica nanoparticles show great potential in the field of tumor diagnosis and treatment because of their unique physical and chemical properties. The drug delivery system based on silica nanoparticles can target tumor tissue passively or actively, and realize the controlled release of drugs in tumor site by stimulating response, effectively improve the concentration of anti-tumor drugs in tumor site, and improve the treatment efficiency. At the same time, silica nanoparticles can achieve the biological imaging function by loading contrast agent, which can be used for tumor tissue localization and drug tracking, and achieve more efficient anti-tumor treatment. In this paper, the preparation methods of silica nanoparticles are introduced, and the research progress of silica nanoparticles in the field of drug targeted delivery system and biological imaging is reviewed.
[Key words] silica nanoparticles; anticancer; drug delivery system; stimulus response; biological imaging
In recent years, the incidence rate of cancer has been rising. Currently, chemotherapy, radiotherapy and surgery have many adverse reactions, such as many adverse reactions, strong relapse and strong multidrug resistance. Therefore, it is very important to develop new treatment methods. A large number of studies [1-3] show that nano drug carriers based on inorganic nanoparticles have great potential in the field of tumor treatment, among which silica nanoparticles (sio2nps) have attracted extensive attention due to their unique physical and chemical properties. Compared with other nanoparticles, the pore structure of sio2nps is orderly and adjustable , its specific surface area is large, and the surface functional groups are easy to modify . These characteristics enable sio2nps to efficiently load drugs, and realize the targeted delivery and controlled release of drugs, becoming an excellent candidate for new nano anticancer drug carriers.
In recent years, the design and synthesis of sio2nps have developed rapidly, and its application in anticancer drug loading, targeted delivery and biological imaging has been in-depth. According to FDA, "silica based nanomaterials are generally safe" . SiO2 NPs, known as "Cornell point" (point C), have been approved by FDA for human clinical trials. In this paper, the preparation of sio2nps and its application in cancer medicine, especially in the field of anticancer drug delivery and bio imaging, are reviewed.
Preparation of 1-sio2 NPS
In the 1990s, sio2nps were synthesized for the first time. With the continuous development of nano particle synthesis technology, sio2nps with different shapes, such as spherical, rod-shaped and lamellar, have been synthesized. Among them, spherical sio2nps has the most potential and the most extensive application research. Spherical SiO2 NPs include solid sphere, hollow sphere and SiO2 NPs with core-shell structure.
Solid SiO2 NPs is usually prepared by sol-gel method. Etching of SiO2 NPs with NaOH etchant can form solid porous silica nanoparticles, which are good carriers for anticancer drugs.
The hollow structure of hollow SiO2 NPs can greatly improve the drug loading, so hollow SiO2 NPs is favored by researchers. Template method is the most commonly used method to prepare hollow sio2nps. The method is based on polymer, inorganic matter, metal complex or organism as templates. The silicon dioxide is coated on the surface of the template by means of assembly, adsorption, deposition and sol-gel method. Then the template is removed by organic solvent dissolution and high temperature calcination, and the hollow SiO2 NPs is obtained.
The core-shell structure of sio2nps is composed of the outer silica shell and the inner material. Its preparation strategy is to prepare the inner material first, and then coat the outer silica shell to form the core-shell structure. Chen et al.  successfully prepared the core-shell structure SiO2 NPs with both the core and the shell of silicon oxide materials using the strategy of "selective etching based on structural differences". FDA has approved the C-point of core-shell SiO2 NPs for clinical trials .
2 SiO2 NPs for drug delivery system
Sio2nps has stable physicochemical properties, high loading capacity, and unique optical, electrical and magnetic properties, which make it an efficient drug delivery carrier. After delivering anti-tumor drugs to tumor tissues, sio2nps can release drugs in a stimulating response way, so as to achieve the purpose of targeted delivery and control drug release, and improve the effect of cancer treatment.
2.1 SiO2 NPs for drug targeted delivery
Traditional anti-tumor drugs without targeting function can not effectively improve the drug concentration of tumor sites, so researchers have been committed to developing drugs that can target tumor sites and improve the drug efficiency. At present, the commonly used tumor targeting strategies are divided into passive targeting and active targeting. Among them, the passive target is based on the enhanced permeability and retention (EPR) , and the active target is based on the over expressed receptor on the tumor cells, using the specific binding of receptor and ligand to achieve the target.
The passive targeting function of SiO2 NPs drug delivery system is based on EPR effect. On the one hand, sio2nps can permeate from the vessels with enhanced permeability in tumor tissue, but not in normal vessels; on the other hand, the efficiency of lymphatic drainage in tumor tissue is reduced, and the residence time of sio2nps in tumor tissue is increased. Using EPR effect, sio2nps drug delivery system can deliver drugs to tumor tissue to a certain extent. To achieve higher specificity, we need to rely on active targeting.
Active targeting requires special design of sio2nps. Sio2nps with specific molecular functionalization can specifically bind to the over expressed molecules in tumor tissue and achieve the active targeting function. At present, it has been found that small molecules, peptides, antibodies, antibody fragments and aptamers can be used to modify sio2nps to achieve active targeting. According to the different target receptors, the active targeting strategies of sio2nps drug delivery system can be divided into tumor cell targeting and vascular targeting.
Targeting of tumor cells is the most commonly used strategy. Functionalized SiO2 NPs can enhance the affinity of tumor cells and deliver loaded drugs to tumor cells. It has been found that sio2nps drug delivery system modified by small molecules (such as folate), aptamers, antibodies, polysaccharides and other substances can specifically target cancer cells and improve drug concentration in tumor tissue. Figure 1 shows a simple schematic of the tumor cell targeting strategy. Recently, Fang et al.  used hyaluronic acid modified sio2nps to recognize CD44 overexpressed on gastric cancer cells, mediate specific tumor targeting, deliver doxorubicin (DOX) and quercetin, and improve drug uptake of tumor cells. Zhang et al.  conjugated cetuximab on the surface of sio2nps to target the over expressed epidermal growth factor receptor in a variety of breast cancer. Part of the anticancer drugs for gene therapy need to be further targeted in the tumor cell nucleus in order to play the anti-tumor role smoothly. Wu et al. Modified sio2nps with TAT (nuclear localization signal peptide) , which can pass through the cell nuclear membrane smoothly and deliver gene drugs to the cell nucleus, so as to achieve the goal of gene therapy.
Figure 1 tumor cell targeting pattern of SiO2 NPs drug delivery system
In addition to targeting tumor cells, another strategy is targeting tumor blood vessels. Because most types of tumor vascular systems have similar properties, the SiO2 NPs drug delivery system targeted by blood vessels can be used in most types of tumors. SiO2 NPs drug delivery system based on blood vessel targeting delivers anti-tumor drugs to tumor vascular endothelial cells, causing them to die, thus cutting off the supply of oxygen and nutrients to tumor tissues. At present, it has been found that arginine glycine aspartate peptide, CD105 antibody and vascular endothelial growth factor 121 can specifically bind to over expressed molecules in tumor vascular system, and their modified sio2nps drug delivery system can significantly enhance the anti-tumor effect.
SiO2 NPs drug delivery system with active targeting function improves the specificity of drug targeting tumor on the basis of passive targeting. Table 1 lists some of the available modifiers for different active targeting strategies. However, due to the complexity of human body environment, the specific action process of sio2nps drug delivery system is not clear. Some studies have shown that sio2nps accumulate in lung, liver, kidney and other organs . The current sio2nps drug delivery system needs to be further modified to avoid the "capture" of human body organs.
Table 1 targeted modifiers of SiO2 NPs drug delivery system
2.2 SiO2 NPs for controlled drug release
With the development of SiO2 NPs in the field of antitumor drug delivery, the potential of SiO2 NPs drug delivery system in drug controlled release has been found by more and more researchers. The nanopore of SiO2 NPs drug delivery system is "blocked" by specific substances, so that the drug does not release or has low release before reaching the tumor tissue. After reaching the tumor tissue, the SiO2 NPs drug delivery system responds to the corresponding stimulation, and the "lock" is opened before drug release. The common stimulation methods are endogenous stimulation and exogenous stimulation.
2.2.1 SiO2 NPs drug delivery system based on endogenous stimulation
In response to endogenous stimulation, sio2nps drug delivery system mainly utilizes the property differences between tumor tissue and normal tissue, such as pH value, redox conditions and enzyme expression.
The pH value of tumor tissue is smaller than that of normal tissue . The abnormal pH value provides signal for pH sensitive SiO2 NPs drug delivery system and triggers drug release. PH responsive SiO2 NPs drug delivery systems often use polyelectrolytes, pH sensitive chemical bonds (such as acetal bond, hydrazone bond, etc.) and small molecules (such as CaCO3) as blocking materials to encapsulate nanopores. In acid condition, the materials are blocked to break down or dissolve, leading to the opening of nanopores and the release of drugs. Recently, samykutty et al.  developed a pH responsive drug delivery system by using chitosan to encapsulate SiO2 NPs. It was found in the mouse ovarian cancer model that the system can significantly increase the drug concentration in the tumor and improve the treatment effect of the tumor.
Redox responsive SiO2 NPs drug delivery systems usually use disulfide bonds sensitive to redox conditions to encapsulate nanopores. When the SiO2 NPs drug carrier reaches the tumor tissue, the disulfide bond is cleaved by glutathione, collagen, cytochrome c, heparin and other redox substances significantly higher than the normal tissue , the nanopore is opened, and the drug is released; before reaching the tumor tissue, the disulfide bond encapsulates the drug in SiO2 NPs, preventing the drug from releasing prematurely.
The SiO2 NPs drug delivery system based on enzyme response uses specific chemical bonds or sequences to encapsulate the nanopores. When the SiO2 NPs drug delivery system reaches the tumor tissue, these chemical bonds or sequences are hydrolyzed by highly expressed enzymes in the tumor tissue, and the drug is released from the nanopores. It has been found that the expression of matrix metalloproteinase, cathepsin B, β - D-galactosidase, elastase and trypsin in tumor tissue is higher than that in normal tissue. Liu et al.  successfully constructed a matrix metalloproteinase responsive drug delivery system based on sio2nps by using substrate peptides sensitive to matrix metalloproteinases, and proved the sio2nps in vivo experiments in mice