*5.2.2 Top-down method*

This method is also known as a destructive method due to the reduction of bulk material to nanometric scale particles. Contrary to bottom-up, large-scale production is possible and chemical purification is unnecessary in the top-down method. Broad size distribution (10–1000 nm), varied particle shapes, control over deposition parameters and reaction costs are disadvantages of this method. There are many techniques in this method, but mechanical milling, nanolithography, laser ablation and sputtering are among the most frequently used ones.

• **Mechanical milling**: This process has been used for a long time in mineral, ceramic processing, and powder metallurgy industries. The aim of mechanical milling of materials consists of minimizing particle size, blending, changing particle shapes, and synthesizing nanoparticles in a high energy mill with a convenient medium. At nanoparticle synthesis elements are granulated in an inert atmosphere. Mechanical milling is an economical method for nanosize production of large quantities [58]. The dynamics of mechanical milling vary according to energy transfer to the material from the balls [59]. Type of mill, the powder

*Immune System Modulations in Cancer Treatment: Nanoparticles in Immunotherapy DOI: http://dx.doi.org/10.5772/intechopen.94560*

supplied to drive the milling chamber, milling speed, size and size distribution of the balls, dry or wet milling, the temperature of milling and the duration of milling are the factors that affect the energy transfer. Also, deformations, fractures, and the type of welding cause variations in particle shape and size [58].

• **Nanolithography**: This is the fabrication of molecules in a nanometric size range of 1 to 100 nm. Lithography is a combination of deposition and etching to have high-resolution topography. There are two main methods called as masked and maskless lithography. These 2 methods contain many techniques inside. While a mask or a mold is needed in masked lithography to fabricate patterns, maskless lithography produces unstable patterns without the use of mask. Photolithography, soft lithography, and nanoimprint lithography are the main techniques in masked lithography. Maskless lithography consists of electron beam lithography, ion beam lithography, and scanning probe lithography [60].

The process is about printing material in a required shape or structure on a light- sensitive material. The main advantage of nanolithography is to make several copies with the desired shape and size from a single nanoparticle. On the other hand, the necessity of some equipment and their costs are the disadvantages of nanolithography [61].

