# Novel Chitosan Derivatives and Their Multifaceted Biological Applications
## 2 Novel ChDs  
Chitosan contains three nucleophilic functional groups: C2-NH2, C3-OH, and C6\(-\)OH. The modification does not initiate changes on the fundamental chitosan skeleton, but results in derivatives that are characterized by new or improved properties. Chitosan can be modified at the amino or C6-OH sites; the C3\(-\)OH groups are not that easy to modify, owing to large steric hindrance. The two-amino groups are easily modified because of their excellent chemical reactivity. Additionally, amino groups of chitosan are more prone to nucleophilic reactions than the OH groups; moreover, both active groups react with electrophilic moieties such as acyl chlorides, acids and halogenated alkanes, which further modify the amino and OH groups non-selectively [19; 20]. Phthaloyl groups and Schiff bases protect the amino group of chitosan [21; 22; 23; 24], and triphenylmethyl, trimethylsilyl, and tert-butyldimethylsilyl are used to protect the OH groups of chitosan [24; 25]. Alkylation (carboxymethylation), acylation (phthaloylation), quaternization, sulfation, thiolation, graft copolymerization, etc. are the predominantly reported modifications tailor-made for specific applications [26]. The major classes of chitosan modifications and what has been achieved through these modifications are briefly summarized below. N-alkylated ChDs comprise diethylmethyl, trimethyl, triethyl and dimethyl ethyl chitosan which emerge following alkylation of the primary amines of chitosan (with suitable aldehyde and reducing agents added). N-trimethyl chitosan (TMC) is prepared via methylation of amine groups with methyl iodide [27]. Its water solubility depends on its degree of methylation [28]. An improvement in the mucoadhesive trait, followed by enhanced absorption (at neutral pH), has been observed in the case of soluble TMC [29; 30; 31]. Quaternized, thiolated, hydrophobic and chemically grafted ChDs are reported to improve or impart novel properties to chitosan. Quaternary ChDs of the N-alkyl or quaternary ammonium types could increase the solubility of chitosan in water and are able to keep its solubility stable over a wide range of pH values. This modification is reported to exhibit enhanced mucoadhesive, drug penetration attributes [32]. N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC) is synthesized by incorporating a quaternary ammonium moiety, such as glycolidyl trimethyl ammonium, into the amine groups of chitosan. This is also what has been used to formulate albumin-loaded chitosan derivative nanoparticles [33]. Other derivatives rise from the addition of hydrophobic groups to chitosan via acylation. Caprylic, lauric and capric acids are the notable fatty acids used to increase the permeability [34; 35]. Oleoyl and octanoylL ChDs are N-acylated ChDs, formed using fatty acyl chlorides; these are resistant to gastric enzymatic degradation and show enhanced mucoadhesiveness and permeability [36]. Thiolated chitosan are produced by modifying the chitosan amine groups with cysteine, 2-iminothiolane, thiobutylamidine or thioglycolic acid. These derivatives possess high drug permeation, improved oral as well as nasal mucoadhesive drug delivery and also displayed in situ gelling behavior in physiological fluids [37; 38; 39]. Trimethyl chitosan-cysteine (TMC-Cy) is a modified chitosan conjugate that combines TMC and thiolated derivatives. This derivative positively impacts chitosan's mucoadhesive and permeation properties. TMC-Cy insulin-loaded nanoparticles are reported to have high insulin encapsulation efficiency and mucoadhesion, compared to TMC-insulin nanoparticles [40]. Chitosan chemically modified through the introduction of carboxylic acid is highly hydrophilic in basic environments. Chitosan succinate and chitosan phthalate showed an insulin-loading capacity of nearly 60% and protection from gastric enzyme degradation [41; 42]. Lauryl succinyl chitosan possesses negatively charged mucoadhesive properties as well as hydrophilic and hydrophobic traits [43].