# Gold Nanoparticles for Drug Delivery and Cancer Therapy
## 2 Synthesis and Properties  
Although there are many methods available to synthesize Au NPs, they are generally synthesized by the colloidal method [21; 22]. This method utilizes a reducing agent, a metal precursor, and a stabilizing agent, which allow an easy tuning of shape, size, and optical properties of the nanostructure. The Au nanostructures that can be synthesized using this method are spheres, nanorods, and nano-cages [23]. Another less common nanostructure being used more recently is the hollow Au NPs, which can be synthesized using galvanic replacement [24]. [PERSON] and [PERSON] developed a one-pot method to synthesize Au NPs, and the method can produce many different monolayer-protected Au NPs in a short period of time [25]. The method utilizes tetrachloroaurate (AuCl4) salt, reduced with sodium borohydride (NaBH4) with the desired ligand. Instead of using NaBH4, citrate can be used as reductant. However, no matter it is the citrate or NaBH4 used in the reduction method, post-treatment (e.g., dialysis) is necessary to obtain the stability and purity of Au NPs [26]. Ligand determines the core size of Au NPs, which is in the range of 1.5-6 nm. If the application requires Au NPs larger than 6 nm, it can be synthesized using other methods such as the ripening approaches or citrate reduction of the Au salt [26]. Another common method for synthesizing monolayer protected Au NPs is the place exchange reaction. This method displaces the ligands of Au NPs in the equilibrium process [27]. For most biomedical applications, the preparation of Au NPs follows the bottom-up method [21; 22; 23; 24; 25; 26; 27]. A method involves the reduction of hydrogen tetrachloroaurate by sodium borohydride or sodium citrate [28]. Stabilizing or capping agents are used to avoid agglomeration and precipitation. Polyethyleneimine (PEI) is a suitable choice of stabilizing agent due to its concurrent role as a delivery and capping agent for nucleic acids. The high density of amine groups and branch PEI enable compound to form NP complexes by reacting to the nucleic acids [29]. PEI-coated Au NPs and their conjugate nucleic acids can be prepared using two approaches: (1) DNA or siRNA condensation onto PEI-capped Au NP monolayer; (2) ionic DNA or siRNA and PEI onto the Au NP core [30]. PEGylation is a process modifying the particle surface area by the Polyethylene Glycol (PEG). This is a common method of reducing the premature clearance of NPs in circulation [31]. Alternative surface medication strategies include conditional PEG removal, substitute polymer and biomimetic modification of surface [32; 33]. A summary of different synthetic methods for Au and other metallic NPs with different sizes can be found in Table 1[21]. At the early stage of using Au NPs, particle size was controlled by varying the ratio of the reducing agents such as sodium citrate, sodium borohydride and hydroxylamine ascorbic acid with HAuCl4. Particle size is tunable by the activity of the Au precursor and power of the reducing agents. A novel approach to change the size of Au NPs in the citrate reduction is to change the chloride ion concentration. The Au NP size can be tuned from 19 to 47 nm using this method [34]. In another approach, Poly(N,N'-diethylaminoethyl methacrylate) was used to stabilize the Au NPs in tetrachloroauric acid with citrates in acidic conditions. In the reacting mixture, the pH has significant \begin{table}
\begin{tabular}{c c c} \hline \hline
**Type of NPs** & **Synthetic Method** & **NP Size (nm)** \\ \hline Au & Sol-gel micro reactors & 5–50 \\ \hline Au, Ag, Pd, Pt & PVD into liquid substrate & 2–10 \\ \hline Pd, Pt & Reduction in acidic environment & 3–40 \\ \hline Au & Reduction process & 2–40 \\ \hline Au, Cu & \(\gamma\)-Irradiation & 3–30 \\ \hline Cu & pH control of Cu complexes & 48–150 \\ \hline Au, Ag, Pd & Biosynthesis & 9–25 \\ \hline Ag & Wet chemistry & 20–60 \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Synthetic methods for different metallic NPs and their typical size distribution [21].