Silica Nanoparticles As Drug Delivery Systems: Essay On Preparation, Biocompatibility, And Toxicity.

Write about the Silica Nanoparticles as Drug Delivery Systems.

a. Preparation/formulation
b. Biocompatibility and toxicity

Formulation

Mesoporous silica has been regarded by scientists as a recent development in the field of nanotechnology that has a huge number of potentials in healthcare. Scientists have conducted extended researches on mesoporous silica and have found their beneficial role in catalysis as well as in drug delivery and imaging techniques. The particles have different types of characteristics like high specific areas, tunable pore structures, high pore volume and also physiochemical stability (1). These characteristics have been previously used by researchers in hydrophilic and hydrophobic active agents. Recently many new features have been established by researchers in different experiments and it has been found that they possess characters of surface functionalization as well as PEGylation. These had made scientists to believe that they can be extensively used as drug delivery vehicle for different types of treatment in cancer patients.

Silica nanoparticles can be prepared by sol gel method. In the first step, they are made to undergo hydrolysis. Then they are combined with head groups of surfactants. Depending upon the nature of surfactant used, the interactions between the surfactant and the silica precursor changes. This interaction thereby varies by forming hydrogen bonding or electrostatic force. The hydrophilic and lipophilic balance with values of span 20, span 40, span 60 are 8.6, 6.7 and 4.3 written in respective manner. The interaction that occurs between the silica precursor and the surfactants are mainly based on value of pH (2). This in turn is found to affect the overall morphology of the articles. Under basic condition it is found that the surfactant of a particular charge and the oppositely charged precursor develops strong interaction resulting in ordered silica particles. A longer duration is observed in cases of neutral conditions when hydrogen bonds are formed between the charged silica precursors and non ionic surfactants.  It has been found by different researchers that when span 60 is used in the Bet method for the preparation of silica nanoparticles, the specific surface area was about  ~11,500 m2/Kg and the particle size was about approximately 80nm. Micrograph that is provided below shows that as the chain length of the surfactant is made to increase, there is decrease in the particle size of the nanoparticles. By using Span 20, span 40 and span 60 in the categories of non ionic surfactants, nanoparticles of size between 150 to 80 nm can be obtained. By using the span series of non ionic surfactant the size can be altered but the ordering cannot be changed. However by the use of other types of non ionic surfactant like Brij 65, both the size and the ordering can be altered.

Bio-compatibility of Silica Nanoparticles

Specific surface area (SSA) of silica nanoparticles synthesized using different surfactants and pH.

The size of the nano particles also depends on the ph system of the reactions. It depends on the concentration of ammonia and higher the concentration of ammonia , Higher is the particle size. With increase in the ph system, particle size increases the rate of monomer addition and polymerization also depends on the ph. When the ph is about 7, it is found that the condensed species get ionized and this results in them becoming mutually repulsive. Above ph 7 the solubility of silica increases, particles are seen to be growing in size due to particle aggregation. It is also seen that there is decrease in number of particles a highly soluble small particles undergo dissolution and then undergo re-precipitation on longer less soluble particles. This is the process called Ostwald ripening.

Stobers’ process is yet another procedure which may be done in two ways with one step process and two step process. Here the precursor of silica called the tetraethyl orthosilicate (Si(OEt)
4, TEOS) is made to undergo hydrolisis reaction in alcohol like those of ethanol and methanol in the presence of ammonia (3). Here ammonia acts as catalyst.

Reactions lead to ethanol and a mixture of ethoxysilols are obtained. This can go further reactions that result in loss of water and alcohol.

On further hydrolysis of the different ethoxy groups, cross linking takes place due to further condensation. This yields granular silica with diameters from 50 to 2000nm. In the second step process, similar procedure takes place where hydrochloric acid is made the catalyst in place of ammonia.

Source:

Silica nanoparticles are used a s vehicle of drug delivery and therefore their safety within the blood system is very necessary to examine.  As they directly come in contact with the tissues and cell directly it becomes extremely necessary to test their biocompatibility.

In an experimental study, researchers took dry powdery particles of silica. All the hydrophilic mesoporous channels of MSNs and MSNs-RhB were actually filled with PBS during the experiment. There was no space left in them which can absorb any further water in the plasma when mixed with it. There it was found that they produced no effect on the coagulation and anticoagulation functions of the plasma. Therefore their hemo-compatability was found to be satisfactory. They are also found to be easily entering the cell and do not affect cell survival also. Their histo-compatability have made the researchers to use them as drug delivery systems and also as biosensors. Scientists like Bardi et al. (2010), have developed NH2functionalisd CdSe/ZnS quantum dot (QD)-doped SiO2 NPs. This has helped in both imaging and gene capabilities. It was seen by the scientists that are internalized by primary cortical neural cells. It was surprising to see that they did not induce any kind of cell death in vivo and also in vitro. Moreover they were also found to be useful due to their ability to bind, transport and at the same time release DNA into cells which helps in GFP plasmid transfect ion of NIH-3T3 and human neuroblastoma SH-SY5Y cell lines (4). Therefore the histocompatability of the silica nanoparticles with the cells were proved. 

Toxicity

Source:

A paper which was published by Lu et al., in the year 2010 showed that fluorescent labeled silicon nana particles showed promising results in biocompatibility. It was administered in mice over a two month study which showed that it had very less effect in the non target organs and showed high success in delivering drug to the target organs having cancer (5). Camptothecin loaded MSNs have an extraordinary capacity to accumulate in tumors releasing the drugs. Moreover they were also found to get released through urine. About 95% of the silica nanoparticles were excreted by the mice body. This is also supported by Fu et al.,  in 2013 who worked on excretion capability as well (6). This showed their high potential as effective drug delivery in future.

It was found through extensive researches that silica nanoparticles have low toxicity when exposed in moderate doses. Therefore they are used extensively in biosensors for assaying of glucose, hypoxanthine levels, l-glutamate and lactate. They are also used as biomarkers in leukemia cell identification. This can be done by using optical microscopy imaging, DNA delivery, Drug delivery and also cancer therapy (7). However cases were reported which showed that these nanoparticles tend to agglomerate and tend to result in protein aggregation when in vitro dose was administered in  25 μg/mL.  Researchers have tried to find out the main reason for this and have stated that oxidative stress sis the main reason behind its cytotoxic effects both in vivo and in vitro. They have mainly provided three important reasons like increase in lipid peroxidation, decreasing cellular glutathione level and increasing production of reactive oxygen species that have contributed to the cytotoxic effects in the cells (8). Researchers have however stated that if such nanoparticles are used in moderate doses, cytotoxicity can be avoided. It has been proved that these nanoparticles may have a contribution to cytotoxicity only when their size and doses are very high (9). They are also dependent upon the cell type in which they are administered. In an experiment conducted by Kim et al. in 2015, it was found that Monodisperse spherical silica nanoparticles (SNPs) when introduced in moderate doses resulted in endocytosis by the cells but at higher doses they result in decrease in cell viability (10). Hence more experiment are required to understand the right doses and sizes of particles and also the cell types where they have negative effects.

Conclusion:

From above discussions, it was found that silica nanoparticles are indeed very much essential as drug delivery vehicles in health care and also act as gene carriers and biosensors. Their high level of biocompatibility is already established. However there is certain toxicity that can rise if used in an improper way like in high doses, sizes and on unknown cell types. Therefore researchers and healthcare professionals should be careful and the same time should be knowledgeable about the features of the nanoparticles to ensure a safe practice. 

References:

1. Li Z, Barnes JC, Bosoy A, Stoddart JF, Zink JI. Mesoporous silica nanoparticles in biomedical applications. Chemical Society Reviews. 2012;41(7):2590-605.
2. Singh LP, Agarwal SK, Bhattacharyya SK, Sharma U, Ahalawat S. Preparation of silica nanoparticles and its beneficial role in cementitious materials. Nanomaterials and Nanotechnology. 2011 Jan 1;1:9.
3. Ibrahim IA, Zikry AA, Sharaf MA. Preparation of spherical silica nanoparticles: Stober silica. Journal of American Science. 2010;6(11):985-9.
4. Bardi G, Malvindi MA, Gherardini L, Costa M, Pompa PP, Cingolani R, Pizzorusso T. The biocompatibility of amino functionalized CdSe/ZnS quantum-dot-Doped SiO 2 nanoparticles with primary neural cells and their gene carrying performance. Biomaterials. 2010 Sep 30;31(25):6555-66.
5. Lu J, Liong M, Li Z, Zink JI, Tamanoi F. Biocompatibility, biodistribution, and drug?delivery efficiency of mesoporous silica nanoparticles for cancer therapy in animals. Small. 2010 Aug 16;6(16):1794-805.
6. Fu C, Liu T, Li L, Liu H, Chen D, Tang F. The absorption, distribution, excretion and toxicity of mesoporous silica nanoparticles in mice following different exposure routes. Biomaterials. 2013 Mar 31;34(10):2565-75.
7. Tang F, Li L, Chen D. Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery. Advanced Materials. 2012 Mar 22;24(12):1504-34.
8. Xie G, Sun J, Zhong G, Shi L, Zhang D. Biodistribution and toxicity of intravenously administered silica nanoparticles in mice. Archives of toxicology. 2010 Mar 1;84(3):183-90
9. He Q, Zhang Z, Gao F, Li Y, Shi J. In vivo biodistribution and urinary excretion of mesoporous silica nanoparticles: effects of particle size and PEGylation. small. 2011 Jan 17;7(2):271-80.
10. Kim IY, Joachim E, Choi H, Kim K. Toxicity of silica nanoparticles depends on size, dose, and cell type. Nanomedicine: Nanotechnology, Biology and Medicine. 2015 Aug 31;11(6):1407-16.