Chitosan Nanoparticles-Based Cancer Drug Delivery: Comparison
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Chitin is the second most abundant biopolymer consisting of N-acetylglucosamine units and is primarily derived from the shells of marine crustaceans and the cell walls of organisms (such as bacteria, fungi, and algae). Being a biopolymer, its materialistic properties, such as biodegradability, and biocompatibility, make it a suitable choice for biomedical applications. Similarly, its deacetylated derivative, chitosan, exhibits similar biocompatibility and biodegradability properties, making it a suitable support material for biomedical applications. Furthermore, it has intrinsic material properties such as antioxidant, antibacterial, and antitumor. Population studies have projected nearly 12 million cancer patients across the globe, where most will be suffering from solid tumors. One of the shortcomings of potent anticancer drugs is finding a suitable cellular delivery material or system.

  • nanoparticles
  • chitosan
  • chitin
  • polysaccharides
  • nanocarriers
  • anticancer agents

1. Introduction

Chitin is the second most biopolymer composed of N-acetylglucosamine units. It is commonly found in higher quantities in arthropods’ exoskeletons, radula of mollusks, and cell walls of fungi [1]. Commercially, it is marketed as one of the components of natural medicinal products, nutraceutical foods, and 3D scaffolds for biomedical and technological applications [2][3]. It is typically produced using a high-temperature method and is reported to exhibit thermostability [4]. Additionally, because chitin shows high tolerance for high chemical concentrations, some metals, such as copper, can be deposited through an electrochemical process at room temperature [5]. Different forms of chitin are present in nature; the side chain’s backbone arrangement determines the difference between the forms of chitins. The α-chitin, β-chitin, and γ-chitin are the three isoforms of chitin [6].

Chitosan (CS), a polysaccharide, is derived from chitin by deacetylation [7][8][9]. Chitosan has been reported for use in various applications, extending from biomaterials and tissue engineering to antibacterial, antifungal, anticancer, and antioxidant agents due to its strong biocompatibility [10]. Chitosan has undergone several chemical changes that have been suggested to give polysaccharides particular qualities. Chitosan samples that have been altered through phosphorylation, quaternarization, carboxylation, sulfonation, N-alkylation, and acylation can function as stimuli-sensitive materials (pH-, thermo-, or light-sensitive) [11]. Chitin and chitosan have been the focus of numerous investigations to determine their efficacy as agents for drug delivery [12]. For instance, chitosan is commonly used for preparing hydrogels for drug delivery due to its essential characteristics, such as bio-adhesion, having a polycationic surface that makes it easier to form hydrogenic and ionic bonds, and biocompatibility, which means it does not generate any toxins or trigger an immune response when in contact with the body fluids or living tissue [13]. Likewise, several types of research have successfully implemented chitin as one of the support materials for drug delivery. However, many ways are reported to transport the drugs, but the implementation of polymeric carriers received a high interest since they increase the effectiveness of drug targeting and extend the time that drugs stay in circulation by reducing urine elimination [14].

2. Extraction of Chitin: Chemical and Biological Process

The cuticles of different crustaceans, primarily shrimp and crabs, are the prime producers of raw material for the formation of chitin. Chitin is a complex protein network component mainly found in crustaceans or shellfish, on which the calcium carbonate accumulates to produce a firm shell [15]. Chitin and protein interact very closely; a minor amount of protein is also contained in a polysaccharide-protein complex. The extraction of chitin from shelf fish primarily requires two-step chemical processing (a) removal of inorganic calcium carbonate by demineralization and (b) removal of proteins by deproteinization. Sometimes, a different decolorization phase is also used to eliminate any remaining pigments [16]. Heat and high alkaline or acidic conditions (>1 M NaOH, >3 M HCl) can cause chitin to change itself into the deacetylated state, chitosan, or hydrolyze into C5 and C6 hydrocarbons [17] on prolonged chemical treatments [1]. Figure 1 shows chitin extraction and chitosan production chemical and biological processes. However, several methods of producing pure chitin have been devised, but no method is accepted as standard procedure to this date. Deproteinization and demineralization could also be accomplished by enzymatic (biological) or chemical processes. Additionally, microbial fermentation is used to simultaneously carry out the demineralization and deproteinization processes [18]. Biological processes, an alternative approach, may produce more satisfactory results because they are inexpensive and environmentally friendly, have low energy usage, and are reproducible. In addition, they can extract or manufacture chitin with greater molecular weight and a more robust crystal structure [19].
/media/item_content/202305/645b53dc14bd6marinedrugs-21-00211-g001.png
Figure 1.
Shows the (
A
) chemical and (
B
) biological process involved in the extraction of chitin and production of chitosan from chitin.

3. Drug Delivery System

Combining an appropriate carrier with one or more drugs is the basic building block of drug delivery systems
[20]
. The two main criteria for perfect delivery systems are concentrating the active substance on the body’s site of action and supplying the correct quantity for a steady, suitable, and predetermined amount of time
[21]
. The first fundamental element of drug delivery systems is keeping plasma drug concentrations under the therapeutic window, accomplished through drug carriers, typically polymers
[21]
. This feature helped to promote the notion of controlled delivery systems. The second characteristic results in the creation of specialized delivery systems. The active substance is captured within a delivery system that may deliver the medicine to the particular site, necessitating careful selection of carrier, route of administration, and target of release
[22]
. The qualities of the medication and polymers, the disease to be treated, the variety of dosage forms, and the method of administration are just among the variables that affect whether delivery systems succeed in achieving their therapeutic goal
[21]
. As carriers, active compounds are frequently delivered using polymers (such as chitin or chitosan). They can be utilized to create various delivery systems, including micelles, hydrogels, tablets, capsules, and particulate systems (beads, micro-, and nanoparticles). The optimized pharmacokinetics usually get considered before choosing an appropriate polymer as it dictates the kinetics of drug release and the removal of carriers following drug delivery
[23]
.

3.1. Rotes of Chitosan Administration

3.1.1. Ocular Drug Delivery of CS

As mentioned above, chitosan’s biodegradability and biocompatibility are important features, making it useful for ocular drug delivery. Chitosan can increase the ocular surface duration of several drugs due to its mucoadhesive nature [24]. It can also transform to gel if smeared on the ocular surface in liquid form as it possesses favorable situ gelling properties. This has led to the therapeutic improvement of ocular drugs. The ocular drugs which are poorly soluble, chitosan nanoparticles (NPs) are a potential alternative, as they can increase the bioavailability of drugs (e.g., naringenin) in the aqueous humor. Moreover, a study by Ping Zhang et al. on rabbit eyes found that chitosan has no irritating effect on the eye [25]. Fluconazole-loaded chitosan NPs were created by Santhi et al., utilizing a cross-linking approach and spontaneous emulsification. They compared the antifungal abilities of these NPs with the traditional eye drops using the cup-plate method. These particles had an average size of 152.85 ± 13.7 nm. All drug-loaded NPs were determined to have an optimal (50%) drug-loading capacity. After completing their research, they deduced that the fluconazole-formulated chitosan NPs were an effective delivery system for fluconazole in drug loading, antifungal efficacy, and prolonged release characteristics [26].

3.1.2. Pulmonary Drug Delivery of CS

The benefits of delivery of drugs to the lungs include immediate and prolonged drug delivery, high effectiveness, and the ability to accomplish both local and systemic effects. Large lung surface area, high vascularity, and a thin absorption barrier are the parameters that improve medication transport via the lungs [27]. Chitosan has been used to enhance the effects of many medications. Rifampicin, an antitubercular medicine, was created as a dry nanoparticle powder inhalation using chitosan as the polymer. This formation demonstrated continuous drug release for up to twenty-four hours without causing any adverse effects on cells or organs [28]. Prothionamide, an antitubercular medication, was given by Debnath et al. as chitosan-coated NPs through the lungs. This change lengthened the drug’s inhalation half-life in the lungs [29].

3.1.3. Mucosal Drug Delivery of CS

Chitosan and its derivatives encourage mucosal delivery by increasing the absorption of hydrophilic molecules such as protein and peptide medicines. The eminently hydrated glycoproteins (lysozymes, salts, and mucins) that make mucus give it its viscoelastic characteristics [30]. To facilitate the paracellular trafficking of macromolecular medicines, chitosan function by opening the compact intercellular junctions. The positively charged, cell-bound chitosan NPs reduce the transepithelial electrical resistance of living cell monolayers and boost paracellular permeability. Depending on the chitosan’s molecular weight and level of deacetylation, the chitosan solution enhances trans and paracellular permeability [31].

3.1.4. Nasal Drug Delivery of CS

Using a non-invasive method like nasal delivery, medications can be administered systemically and locally without experiencing the normal gastrointestinal problems associated with oral management or the effects of hepatic metabolism [32]. Although nasal management can cross the blood–brain barrier (BBB), which has been shown to guide drug delivery from the nose to the brain (NTB) efficiently, NTB is an alternate way of topical management for antibacterial and anti-inflammatory nasal congestion [7]. One of three pathways (three methods of nasal absorption) allows nasally administered drugs to instantly cross the BBB: first, olfactory nerves, which are the foremost effective pathway for NTB delivery of drugs; second, trigeminal nerves, which have the presence of nerve endings in the respiratory epithelia; and third, respiratory epithelium. Some limitations of NTB delivery include the minor volume of the nasal cavity, enzymatic degradation, mucociliary clearance, short drug retention duration, potential nasomucosal toxicity, drug management and deposition technique, and the need for an appropriate delivery device [33]. Due to their limited permeability, the nasal epithelium is challenging to penetrate with hydrophilic medicines, nucleic acids, proteins, and peptides. CS enhances their permeability. The drug’s weight, lipophilicity, and charge affect how well it is absorbed through the nose. The mucociliary system clears medications that cannot pass the nasal membrane. Due to its use in nasal delivery, CS has mucoadhesion qualities combined with low toxicity, biodegradability, and biocompatibility, which can assist in resolving this concern [32]. To increase drug concentration in the active site, direct therapeutic material delivery to the brain is necessary for neurologic illnesses such as Parkinson’s disease (PD). In the central nervous system, PD is characterized by neurodegeneration and dopaminergic neuron loss in the CNS. The current standard of care for managing PD motor symptoms relies on the dopamine (DOPA) replacement strategy, which tries to compensate for the death of dopaminergic neurons and restore adequate neurotransmitter levels. Due to elevated hydrogen-bonding potential, complete ionization in physiological pH, and significant metabolism when administered orally, it is challenging for DOPA to penetrate the BBB. The development of DOPA-loaded nanocarriers as a novel mechanism for treating Parkinson’s disease has received the most significant attention [34]. These nanocarriers should have the capability to traverse BBB and permit persistent transport of the neurotransmitters to the brain. 

3.1.5. Transdermal Drug Delivery of CS

A transdermal drug delivery system is being evolved to overcome the shortcomings of traditional administration methods. The limited skin permeability is the fundamental obstacle to be addressed when creating transdermal dosage forms. Several techniques have been devised to get around the barrier qualities and improve the transportation of medication molecules over the skin [35][36][37]. Numerous transdermal patches made of polysaccharides have been discovered in recent years. Transdermal preparations containing CS are becoming more widespread [37]. NPs have been promoted as one of the prospective delivery systems that can significantly overcome the constraint of the drug’s ability to penetrate the skin.

3.1.6. Dermal Delivery of CS

The systemic unpropitious effects of traditional oral and injectable delivery could be avoided with topical treatment. Additionally, this can swiftly and directly penetrate the skin and mucous membranes at the illness site [7]. Since they enable the regulated release of drugs and address the issue of their low skin bioavailability, NPs are seen favorably for treating acne. Nicotinamide is one of the potential cosmeceuticals/nutraceuticals lately utilized to treat acne. This medication has anti-inflammatory effects and is said to reduce sebum production.

3.1.7. CS Administration for Wound Healing

Various bacteria can infect and colonize injured skin, making it easier for them to get to the underlying tissues [38]. One crucial element that is thought to slow the healing of wounds is infection. In addition to providing a moist surrounding to prevent wound dryness, reducing wound surface necrosis, being oxygen penetrable without dehydrating the wound, and being congenial, wound dressings should also prevent mechanical damage [39]. Less toxicity, biocompatibility, and biodegradability are further important requirements for a material used to make wound dressing [40]. It has been demonstrated that the N-acetyl glucosamine, which is a monomer unit of CS, promotes cell growth, promotes hemostasis, as well as speeds up the healing of wounds.

54. Chitin and Chitosan for Drug Delivery and Cancer Treatment

Drug development and delivery have seen significant breakthroughs due to nanotechnology. For instance, the utility of NPs in the treatment and diagnosis of cancer has advanced to the point where it can now detect and target a single cancer cell with the delivery of a carrier to treat it. Traditional cancer therapeutic techniques include side effects, and diagnostic procedures are expensive and time-consuming. Due to their large size, surface charge, and morphology, NPs such as carbon nanotubes (CNTs), calcium NPs (CaNPs), graphene, and polymeric NPs (including chitin and chitosan) have improved cancer diagnostics and treatments. These NPs functionalization with various biological molecules, such as antibodies, aids in the transportation of drugs and the detection of cancerous cells [41]. Chitin holds the ability to generate as a drug delivery system and anticancer agent. It has been demonstrated that chitin can suppress chitinase-3-like protein-1 (CHI3L1), which is overexpressed and stimulates proinflammatory mediators in breast cancer cells [42]. Moreover, the synthesis of vascular endothelial growth factor C (VEGF-C), associated with tumor angiogenesis, can be downregulated with chitin [43]. Chitin has been formed in several kinds that can counteract cancer. For example, cytotoxicity was promoted in human breast cancer cells (MCF-7 Cells) with chitin nanocomposites embedded with silver [44]. Curcumin is an active turmeric substance with anticancer, antibacterial, and antifungal properties [45]. Curcumin-loaded chitin nanogels (CCNGs) is an anticancer drug with chitin and curcumin and are insoluble in water. It has been seen that CCNGs-prepared materals, when treated on porcine skin samples, showed easy penetration in the epidermis od the skin with no signs of inflammation. This shows that the formulation of CCNGs can treat melanoma, which is one of the most serious and common types of skin cancer [46]. Cancer vaccine has evolved as a unique cancer treatment method with the emergence of cancer immunotherapy, and the significance of adjuvants has lately been recognized. Adjuvants are chemical compounds that boost immunity and promote a vaccine’s potency without exhibiting any direct antigenic consequences of their own [47]. In addition to the previously listed applications, chitin and chitosan are essential adjuvants for immunotherapy. Many studies have investigated the adjuvant characteristics of chitin and chitosan due to their immunostimulant capability and structural resemblances to glucans, a subsidiary type of natural polysaccharides [48]. Chitin and chitosan’s antiviral and anticancer properties were first described decades ago. Suzuki et al. initially showed the adjuvant action of chitin and chitosan in the 1980s [49]. Chitin and chitosan are frequently used for non-invasive mucosal management routes, such as oral, intranasal, and ocular mucosa, due to their mucoadhesive characteristics [50]. Specific antigens have been demonstrated to boost adaptive immune responses [50]. Recent studies have shown that chitosan is a potential adjuvant for intranasal vaccination [51]. Moreover, chitin has a size-dependent and complex effect on adaptative and innate immune response, including the capability to activate and recruit innate immune cells, which stimulates chemokine and cytokine production [52]. It has been seen that IL-12 is an antitumor cytokine that induces toxicity upon systematic administration. IL-12 can be formulated with chitosan (chitosan/IL-12) and administrated (intratumorally) in tumor mice model, could help in limiting the systematic toxicity by enhancing the local retention in the tumor microenvironment of the IL-12 [53]. Moreover, the delivery of most of the NPs or nanocarriers, including chitin and chitosan, is of two types: the passive targeting of NPs for drug delivery and the active targeting by NPs for drug delivery. The passive drug delivery of chitosan for cancer treatment is explained in (Figure 32) and the active drug delivery of chitosan for the treatment of cancer is explained in (Figure 43).
/media/item_content/202305/645b5406a7e8bmarinedrugs-21-00211-g003.png
Figure 32.
Shows passive targeting of CS nanocarriers for drug delivery against cancer cells.
/media/item_content/202305/645b541f9d7d6marinedrugs-21-00211-g004.png
Figure 43. The functionalization of the surface of NPs specific to the ligand is one of the critical features of active targeting. The ligand selected should be specific to the overexpressed receptor at the surface of cancer cells. The figure shows that the ligand of chitosan nanocarriers binds to the overexpressed receptor of cancer cells; after binding, the receptor-mediated endocytosis takes place, leading to the formation of the endosome, and then the dependent release of drugs will happen. Once the pill is released, the cell will proceed under apoptosis through DNA damage, translation block, and cell cycle arrest.

65. Advantages of Using Chitin and Chitosan in Nanomedicine

6.1. Biocompatibility

5.1. Biocompatibility

Chitin and chitosan can be utilized effectively in the human body without having any negative effects because they are biodegradable and biocompatible. They are, therefore, suitable for a range of biomedical applications, such as wound healing, tissue engineering and medication delivery. Chitin and chitosan have been utilized to create polymer scaffolds. Furthermore, there is growing interest in using chitosan to create nanocarriers and facilitate microencapsulation techniques for the transport of medications, biologics, and vaccines [10][54]. The chitin and chitosan are useful as they can be created as chitin or chitosan-based nano- and micro-particles with certain sizes and cargo-release properties [54].

6.2. Antimicrobial Characteristics

5.2. Antimicrobial Characteristics

Research has revealed that chitin and chitosan exhibit antimicrobial action against a variety of pathogens, including fungi, bacteria, and viruses. Due to this characteristic, they can be used to create antimicrobial coats for medical equipment and to treat infectious conditions [55][56][57]. Moreover, chitosan films have also been employed as a packaging material to maintain the quality of a wide range of food items [58]. Chitosan exhibits strong antibacterial properties against both Gram-negative and Gram-positive bacteria, fungus, and other pathogenic and spoilage micro-organisms [59][60].

6.3. Mucoadhesive Characteristics

5.3. Mucoadhesive Characteristics

Chitosan and chitin contain mucoadhesive capabilities, which means they could cling to mucosal membranes that are found in the nose, mouth, and gastrointestinal system. Chitosan and chitin can be developed into medication delivery systems for oral and nasal administration because of this characteristic. The use of chitin and chitosan as the vehicles for mucoadhesive system drug delivery has a significant impact that further emphasizes the potential advantages of increased therapeutic agent bioavailability, prolonged drug residence time at the site of administration, and comparatively quicker drug absorption into the systemic circulation [61].

6.4. Biodegradability

5.4. Biodegradability

Chitin and chitosan can be converted into non-toxic chemicals by the body’s natural mechanisms since they are biodegradable. They are the perfect choice for use in drug delivery systems that call for a sustained drug release over a long timeframe because of this attribute [62]. According to current research, lysozyme and bacterial enzymes in the colon are the main degraders of chitosan in vertebrates [63]. Many different microbes produce and/or breakdown chitin [64].

76. Problematics of Chitin and Chitosan in Nanomedicine

7.1. Allergenicity

6.1. Allergenicity

It has been demonstrated that chitin and chitosan can cause allergic reactions in some people by inducing an immunological response. Therefore, its usage in some biological applications may be constrained by this fact. Unfortunately, chitin-chitinase-stimulated hypersensitivity is a common cause of occupational allergy. Moreover, current research has studied the immunologic effects of chitin both in vivo and in vitro, and these investigations have shown new facets of how chitin regulates innate and adaptive immune responses. It has been demonstrated that exogenous chitin controls adaptive type 2 allergic inflammation in addition to activating macrophages and other innate immune cells. These results further show that chitin interacts with many cell surface receptors, including the macrophage mannose receptor, to activate macrophages [65].

7.2. Limited Solubility

6.2. Limited Solubility

Chitin and chitosan’s utility in various applications may be restricted by their inability to dissolve in neutral pH water. Yet, by altering their chemical makeup or using the right solvents, solubility can be increased. The degree of acetylation, pH, temperature, and polymer crystallinity are some of the variables that affect how soluble chitosan is [66]. The lower solubility of chitosan was attributed to the polymer’s increased crystallinity following deacetylation, which counterbalances the effect of the polymer’s increased glucosamine moieties. On the other hand, the half-acetylated sample showed a decrease in crystallinity. The solubility window of chitosan is also changed by the application of hydrogen bond disruptors such as urea or guanidine hydrochloride. In actuality, wide solubility is accomplished by combining chemical and physical disruption of the hydrogen bonds [67].

7.3. Variability from Batch to Batch

6.3. Variability from Batch to Batch

Depending on the source and preparation techniques used to create chitin and chitosan, its characteristics can change. This may result in batch-to-batch variability, which may have an impact on some applications’ ability to reproduce and maintain consistency in their results [68].

7.4. Limited Stability

6.4. Limited Stability

Recently, a lot of studies have been put into creating reliable and safe chitosan products. Unfortunately, the issue of chitosan-based systems’ weak stability limits their practical applicability; as a result, it has become extremely difficult to produce chitosan formulations’ adequate shelf-life [66][68]. The degree of chitosan purity has a significant impact on the substance’s solubility and stability in addition to its biological characteristics such as immunogenicity or biodegradability. Moreover, chitosan’s stability is affected by a number of variables, including the degree of deacetylation, moisture content, and molecular weight. Similarly, the stability of chitin is also limited; however, cross-linking chitin with enzymes or other chemical compounds can help in the upgradation of the stability of chitin [66].
 

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