# Sol-Gel Silica Nanoparticles in Medicine: A Natural Choice. Design, Synthesis and Products
## 3 Silica NP Design
### NPs Synthesis Methodologies
#### 3.3.3 Solution Route
Among the commonly used functionalizing groups, amine (-NH\({}_{2}\)) is the first choice when gene transfection is designed for gene therapy or vaccination. The -NH\({}_{2}\) groups electrostatically interact with proteins, enhancing their absorption, biding and protecting pDNA from enzymatic digestion allowing cell transfection in vitro. ORMOSIL NPs have great potential in DNA delivery; ORMOSIL transfection efficiency was equal to or even better than Herpes Simplex Virus-1 (HSV-1)) and does not cause any damage to the tissue nor has immunological side effects that have commonly been observed with viral-mediated gene delivery [144]. ORMOSIL NPs crossed the blood brain barrier (BBB) in fruit fly insects [145] where no toxic effects on the whole insect organism or their neuronal cells were observed. Biodistribution and clearance in vivo studies (mice) using ORMOSIL NPs showed a greater accumulation in liver, spleen and stomach than in kidney, heart and lungs. Although, clearance studies carried out over 15 days period indicated hepatobilary excretion of the NPs in the same mice [146]. Core-shell structures have great potential in future biomedical applications, since they constitute a scaffold to create multifunctional NPs, applied to several medical fields, from theranosis to gene delivery performance. Sol-gel Stober method, by simply replacing the nucleating agent SSS (commonly used in the synthesis of plain SiO\({}_{2}\) NPs) by another nanosized system, enables its coating. Superparamagnetic iron oxide NPs (SPIONs) [48], and liposomes [147] are selected nanosystems, due to their academic and industrial relevance (Figure 10). SPIONs, the only clinically approved metal oxide NPs [48], have an excellent response to external magnetic fields. However, administration route and SPIONs surface properties dictate their ultimate effect in terms of the efficiency of cellular uptake, biodistribution, and potential toxicity. SPIONs with hydrophobic surfaces are rapidly and efficiently opsonized and cleared from mammal's circulation system, while SPIONs with hydrophilic surfaces resist these processes being slowly cleared. Silica/ORMOSIL coating emerge as an interesting coating material, granting hydrophilic surface properties, decreasing SPIONs high aggregation tendency, protecting SPIONs from oxidation and thus increasing their blood circulation time [148]. Liposomes are excellent carriers due to their capacity to load hydrophilic and/or hydrophobic molecules, to penetrate in altered vasculatures (due to pathological situations like in cancer or inflammation), to drug release at target sites (over prolonged periods which may vary from hours to weeks) [149]. In clinic, for intravenous administration, there are already several pharmaceutical systems where drugs are encapsulated in liposomal structure. However, when oral administration is envisaged and gastrointestinal tract mucus and epithelium barrier need to be overcome, the protection of liposomes from anticipated disruption becomes a promising strategy [150]. The emerging of silica-based drug delivery carriers for oral route administration was the _leitmotiv_ for silica-coating of liposomes, LIPOSIL for short [151]. Simply silica hollow-sphere NPs (another core-shell possibility) are capable of carrying large amounts of payload or fill their cores with other desirable materials such as polymers, gold or silver along with the gene delivery performance. They can be created through the condensation of alkoxysilanes onto polymer based templates, metal organic frameworks or other nanomaterials, lately removed by chemical etching or thermal degradation [150].