# Sol-Gel Silica Nanoparticles in Medicine: A Natural Choice. Design, Synthesis and Products
## 3 Silica NP Design
### NPs Physiologic Barriers  
The biological performance (pharmacokine profiles, biodistribution, target recognition, therapeutic efficacy, inflammatory reactions and toxicity) of intravenously injected NPs is controlled by a complex array of interrelated physicochemical and biological factors, starting with _opsonization_, followed by _phagocyte_ ingestion and ending with NPs _clearance_. [81; 82; 83; 84]. Rapid blood clearance limits drugs/gene/therapeutic molecules/markers accumulation at target delivery sites, while NPs accumulation in macrophages (within clearance organs) initiates inflammatory responses, inducing toxicity [85]. Opsonization is the process by which a foreign organism or particle becomes covered with biologic proteins (opsonins), forming a coating (named _corona_ by materials scientists or _opsonins_ in pharmaceutics) thereby making it more visible to phagocytic cells. The exact mechanism through which opsonization is activated is complex and is not yet fully understood. When the opsonin proteins (blood serum components like laminin, fibronectin, C-reactive protein, type I collagen, components of the complement proteins such as C3, C4, and C5 and immunoglobulins [81; 82]) come into close contact with engineered NPs, typically by random Brownian motion, they may adsorb on NPs surface through van der Walls, electrostatic, ionic or hydrophobic/hydrophilic attractive forces. Protein opsonization usually takes place in the blood circulation system and may hold from few seconds to many days to complete. After opsonization, phagocytosis occurs. Macrophages (typically Kupffer cells of the liver or spleen) cannot directly identify the NPs themselves, but rather recognize (through specific, non-specific receptors or complement activation) opsonin proteins adsorbed to the NPs surface [81]. Macrophages may uptake foreign materials within a matter of minutes (after opsonization), increasing the phagocytosis rate for positively charged and bacteria-specific proteins and render them ineffective as nanocarriers [83]. Finally clearance occurs. The phagocytes begin to secret enzymes and other oxidative molecules (like superoxides, oxyhalide molecules, nitric oxide, and hydrogen peroxide) to ingest (chemically break down) the phagocytosed material [81]. Unfortunately, most non-biodegradable NPs cannot be degraded significantly by this process and, depending on their relative size and molecular weight will either be removed by the renal system or sequestered and stored in one of the mononuclear phagocyte system (MPS) organs. Renal clearance (based on physical filtration, dialysis) is a second optimal method for expelling NPs from the body. As a first approximation, removal by the renal system occurs only for polymeric molecules with a molecular weight of around 5000 or less, or inorganic NPs with hydrodynamic diameters smaller than 8 nm. Dendrimers (with molecular weights as high as 100,000) and NPs larger than 8 nm (if somehow broken down into fragments smaller than 6 nm after drug release) may also be cleared by the renal system [86]. Non-biodegradable NPs and degradation molecules with a molecular weight higher than the renal threshold typically become sequestered in the MPS organs (Figure 4). Several methods have been developed to mask or camouflage NPs from the MPS or renal clearance. The most preferred of these methods is the adsorption or grafting of poly (ethylene glycol) (PEG) to the surface of NPs. Addition of PEG and PEG-containing copolymers to the surface of NPs resulted in an increase in the blood circulation half-life of the NPs by several orders of magnitude. This method created a hydrophilic protective layer around the NPs that is able to repel the absorption of opsonin proteins via steric hindrance, thereby blocking and delaying the first step in the opsonization process [81].