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The gold nanoparticles used for the delivery of drugs or other medical purposes are in their aqueous form (Bhumkar, et.al., 2007). Aqueous gold nanoparticles are synthesized via the Turkevich method using inorganic reactants, or the Brust-Schiffrin method using organic solvents. Both methods lead to the formation of excellent uniform gold nanoparticles but generate gold nanoparticles with different core size, functionality and interactions with insulin. Uniform gold nanoparticles are desirable because that indicates that the surfaces chemistries of gold in the nanoparticle will be equally reactive.

There are several synthetic methods had been developed to form gold nanoparticles of varing care size (Ghosh, et. al., 2008): (Brust-Schiffrin method*) || Alkanethiol || (Turkevich method*) || Citrate ||  __**Synthesis of thiol stabilized gold nanoparticles using the Brust-Schiffrin Method (Zhou et al. 2009):**__ 
 * Core size (nm) || Synthetic methods || Capping agents ||
 * 1-2 || Reduction of AuCl(PPH3) with diborane or sodium borohydride || Phosphine ||
 * 1.5-5 || Biphasic reduction of HAuCl4by sodium borohydride in the presence of thiol capping agents
 * 10-150 || <span style="font-family: Arial,Helvetica,sans-serif; font-size: 110%;">Reduction of HAuCl4 with sodium citrate in water



<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Brust-Schiffrin method was developed by Brust and Schiffrin in 1994, the reactions was shown as above. Au(III) is reduced to Au(I) by oxidizing alkanethiols (RSH) to form Au(I) thiolate complex. The gold salt transfers from an aqueous phase to an organic phase using tetraoctylammonium bromide (TOAB) as the phase-transfer agent. The gold nanoparticles are stabilized in the organic phase by the alkanethiol ligands. These gold nanoparticles are thermally and air stable due to the monodispersed gold nanoparticle being capped by densely packed monoloayers (Zeng and Zhang 2009)The particles size is depend on several factors such as (gold : thiolate) ratio, temperature, and the rate at which the reduction is conducted (Zhou et al. 2009).

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">The ligand replacement reaction allows a variety of groups to be functionalized on the particle surface where insulin can be adsorbed at the surface of the polymer or entrapped in the polymer. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 110%;"> <span style="font-family: Arial,Helvetica,sans-serif; font-size: 110%;"> Figure 3: Schematic Representation of Insulin encapsulated or absorbed at the surface of a nanoparticle.

Nanospheres contain polymeric structure inside, and insulin may be entrapped inside the sphere or absorbed at the surface. For the nanocapsule, insulin maybe be entrapped inside the system or adsorbed at the surface as well, but it most commonly exists as entrapped inside the inner core of the capsule (Damge 2008). Although both the encapsulation and adsorption of insulin onto the gold nanoparticle are both possible, there is reason to believe that encapsulation would result in the destruction of the nanoparticle in order to eject insulin into the receptive site. Thermodynamically speaking, the surface adsorbed insulin is expected to be more favourable, as less energy is required to eject insulin from the nanoparticle onto the receptive site. However, this theory is that of the student, an further research needs to be conducted to prove or disprove this theory.

__**Synthesis of Nanoparticles using the Turkevich Method:**__

The Turkevich method involves the reduction of gold trichloride with trisodium citrate (Bhumkar, et.al., 2007). To perform this reduction, tetrachloroauric acid is dissolved in deionized water and boiled. The solution of sodium citrate is added to the hot gold solution and heat is supplied to the solution for an additional thirty minutes. The reduction of tetrachloroauric acid is observed when the solution changes colour. The colours observed during reduction are grey, blue, dark purple, until it settles into the deep red colour. Trisodium citrate acts as the reducing agent in this reaction.

Recently, there have been modifications made to the original Turkevich method. A study shows that semi-spherical gold nanoparticles can be synthesized using silver (I)-assisted citrate reduction of tetrachloroauric acid (Xia and Wang, 2009). This reaction proceeds by mixing tetrachloroauric acid (0.5 wt %) with silver nitrate (0.1 wt %), and adding to a citrate solution (1 wt %) while stirring. Water is added to this mixture and is incubated for five minutes prior to the addition of hot water. Following the addition of hot water, colour changes are observed. The same colour changes as in the original Turkevich method are observed.

The reaction scheme below portrays in detail the different chemical reactions that are taking place during the reduction of the tetrachloroauric acid. Addition of sodium citrate with tetrachloroauric acid results in the oxidation of the former to sodium acetate dicarboxylate (SADC) and the reduction of the latter to AuCl. Meanwhile, depending on the pH values of the solution, the tetrachloroauric acid is hydrolyzed to give many forms of its ion, as observed in the first portion of the scheme.

The addition of citrate to the tetrachloroauric acid also serves as a buffer depending on the amount and concentration of citrate added. Nucleation and crystallization of gold nanoparticles occurs rapidly at high temperatures. However, the buffer effects of citrate encourage the crystal growth of the nanoparticles. The two factors mentioned above act independently, and this results in the formation of varying sized of gold nanoparticles (Xia and Wang, 2009). Synthetically, the uniform and smooth nanoparticles are desired, and the specific sizes are synthesized for different medical purposes. Thus, measures are taken to reduce the pH buffer effects by adding the tetrachloroauric acid mixture to 50 mL of boiling water, rather than adding the citrate solution to boiling tetrachloroauric acid solution

Figure 4: Reactions involved during the Citrate Reduction of tetrachloroauric acid for nucleation and crystal growth of gold nanoparticles.
 * SADC= Sodium acetate dicarboxylate.

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