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Chitosan-Based Nanoparticles for Drug Delivery

Elham Rostami

Shahid Chamran University of Ahvaz, Department of Chemistry, Faculty of Science, Ahvaz, 61357-43337, Iran

1.1 Introduction

Drug delivery systems are defined and designed for targeting cells and for using carriers to deliver the drugs, such as bioactive compounds, in a controlled manner to reduce or even remove side effects of drugs and undesirable interactions. Another purpose of the drug delivery system is to prolong the drug release to modify cure process efficiency [1].

Among the polymers being used in the drug delivery system, chitosan has shown significant properties. Chitosan is a linear semicrystalline natural polysaccharide used for drug delivery systems earned from acylation of chitin (Figure 1.1) and may consist of N-acetyl glucosamine and glucosamine to compose the partially or fully deacetylated chitosan polymer (Figure 1.2) [6-8].

Figure 1.1 Deacetylation process of chitin.

Figure 1.2 (a) Partially deacetylated chitosan polymer and (b) fully deacetylated chitosan polymer. Hydroxyl and amino groups of chitosan are particularly use in modified attachment of molecules to chitosan via polymerization processes wide achievements are led by chitosan properties such as biocompatibility, biodegradability, nontoxicity and high charge density [2, 3]. Also, the Food and Drug Administration (FDA) has approved the safety of chitosan using in biomedical and pharmaceutical fields [4, 5].

Sources: Kenawy et al. [2]; Kumar et al. [3]; Muzzarelli [4]; Swetha et al. [5].

According to the fractions of glucosamine and N-acetyl glucosamine, increasing each of the fraction results in different terms. First term is the degree of deacetylation (DDA), which shows higher fraction of glucosamine units within the polymer called the chitosan. In contrast, the greater fraction of N-acetyl glucosamine units shows the second term, the degree of acetylation (DA) commonly referred to as the chitin [9, 10]. The solubility of the polymer in aqueous acidic media depends on chitosan proportion. In other words, the protonation of free amino groups provided by chitosan makes the solubility of polymer feasible in aqueous acids, although chitosan is not ordinarily soluble in alkaline media [11].

Hydroxyl and amino groups of chitosan are particularly used in modified attachment of molecules to chitosan via polymerization processes. Wide achievements are led by chitosan properties such as biocompatibility, biodegradability, nontoxicity, and high charge density [2, 3]. Also, the Food and Drug Administration (FDA) has approved the safety of chitosan being used in biomedical and pharmaceutical fields [4, 5].

1.2 Chemical and Biological Properties of Chitosan

The significant chemical and biological properties of chitosan such as large surface area for drug loading, transfection, and permeation-enhancing effect provide a wide range of possibilities to deliver the drug more efficient due to reactive amino groups and availability of hydroxyl groups in the chitosan molecule [12, 13]. The solubility of chitosan polymer is different and depends on the DDA, protonation of amino groups, and pH range. Dissolving chitosan in dilute organic acids is a way possible in comparison to the inorganic acids [14]. The application of chitosan in pharmaceutical formations are expanded, especially when it is modified chemically and enzymatically to prepare its polymer derivatives with new properties to be used as drug carrier over a wide pH range [15].

Preparation of scaffolds, nanoparticles (NPs), beads, and many other forms (Figure 1.3) of chitosan are due to such adaptable characteristics.

Figure 1.3 Possibilities of chitosan processing.

Whereas special biomedical and pharmaceutical applications of chitosan due to its physicochemical and biological properties provided additional function compared with other polymeric biomaterials, the reactivity and processability of this cationic polysaccharide shows some limitations, such as being water soluble, which is an experienced fact at neutral pH and is a major limitation that is recently developed with modified chitosan preparation. For physicochemical improvement of chitosan, a surface modification technique to make solubility more possible and also to utilize other properties is operated. There are many reported methods for chitosan modification, which will be discussed in the following text [16, 17].

Two main methods are chemical modification and physical interaction. Chemical modification introduces attaching new functional groups to the backbone, like photosensitizers, dendrimers, sugars, cyclodextrins, and crown ethers, or improving the current groups (Figure 1.4). However, chitosan itself is used in biomedical application due to its many great properties. Via modification of chitosan, many special goals are achieved such as targeting specific issues, controlled drug delivery, and enhancing antimicrobial efficiency [21-25].

Figure 1.4 Chemical modification and applications.

Sources: Kumar et al. [3]; Sayın et al. [18]; Satheeshababu and Shivakumar [19]; Martien et al. [20].

1.2.1 Chemical Modification of Chitosan

The low solubility of chitosan is a limitation against great properties of chitosan. This insolubility occurs in many solvents at neutral or high pH excluded organic solvents. There are many reasons for this low solubility, such as inflexible physical properties and low concentration of antioxidant molecules due to scarceness of H-atom donors [26, 27]. Modification of chitosan addresses this problem. The first and major purpose of modifying chitosan is to synthesize soluble derivatives in neutral and basic environment. Moreover, modification of chitosan is for controlling attached functional groups and ligands to the chitosan backbone and especially for controlling its hydrophobic, cationic, and anionic properties. The possibility of modification process in chitosan is caused by the functional groups attached on chitosan molecule such as primary and secondary hydroxyl and amino functional groups [28].

There are methods to chemically modify chitosan: first is the chemical linkage of chitosan, which introduces combination of chitosan and synthetic or natural polymers [29], and second is the chemical grafting of chitosan, which is a graft copolymerization that makes side chains on polymer to prepare a new natural or synthetic derivative. This operation is possible in many ways such as ceric ion initiation, energy radiation, and nonradical-based reactions [30].

Many valuable properties of chitosan also remained in derivatives of chitosan, which have large applications in biomedical and pharmaceutical purposes. These features are biodegradability, biocompatibility, and mucoadhesion [31-33].

Few chitosan derivatives are shown in Figure 1.4.

1.3 Biomedical Applications of Chitosan and Its Derivatives

Using chitosan and its derivatives has been recently investigated and developed as a new field of study in drug delivery systems due to their great biomedical properties. Some of applications are introduced and discussed in the following subsection.

1.3.1 Chitosan Derivatives

1.3.1.1 Carboxymethyl Chitosan

The most explored chitosan derivative is the carboxymethyl chitosan (CM-chitosan) with depending solubility on pH known as amphoteric feature of the polymer. CM-chitosan can be prepared by controlled conditions of the reaction of sodium monochloroacetate with sodium hydroxide. Products of this reaction are O-carboxymethyl (Figure 1.5) and N-carboxymethyl chitosan (Figure 1.6) [8].

Figure 1.5 Preparation steps of O-CM-chitosan (O-CMC).

Source: Based on Rinaudo [8].

Figure 1.6 Preparation steps of N-CM-chitosan (N-CMC).

Source: Based on Rinaudo [8].

However, O-substitution is favorable only at room temperature, while in higher temperature, N-substitution is the adopted route. Alternative derivatives, N,N-critical micelle concentration (CMC) and N,O-CMC, are also products that can be used depending on conditions and reagents. The two other blended CM-chitosan derivatives are illustrated in Figure 1.7. [34].

Figure 1.7 N,N-CMC and N,O-CMC.

Source: Modified from Andrade et al. [34].

Using CM-chitosan nanoparticles as carriers for some particular anticancer drugs is recently investigated. In one study, Shi et al. worked on iontropic gelification with calcium ions, so they designed a variety of CMC derivatives with different molecular weight...