Elsevier

Journal of Controlled Release

Volume 317, 10 January 2020, Pages 216-231
Journal of Controlled Release

Review article
Stimuli-responsive chitosan as an advantageous platform for efficient delivery of bioactive agents

https://doi.org/10.1016/j.jconrel.2019.11.029Get rights and content

Highlights

  • Chitosan, its properties and modification with a variety of stimuli responsive units are discussed.

  • Responsive behavior of chitosan based systems using internal and external stimuli is reviewed.

  • Discussion of literature on stimuli responsive chitosan based systems in drug delivery in vitro and in vivo, is provided.

Abstract

Despite a diverse range of active pharmaceutical agents currently at our disposal, high morbidity rate diseases continue to pose a major health crisis globally. One of the important parameters in this regard is the controlled cargo delivery at desired sites. Among a variety of synthetic and natural macromolecular systems, chitosan, an abundant biopolymer, offers a platform for tailored architectures that could have high loading capacity of cargo, target and deliver. Stimuli directed accumulation of vehicles and drug release is an area of direct relevance to biomedical applications. In this review, we highlight essential characteristics of modified chitosan that present themselves for efficient response through an internal (glutathione, reactive oxygen species, pH, temperature, enzymes, and chemical/electrical potential gradient), and external stimuli (ultrasound, light, mechanical stimuli, magnetic and electrical fields). With a brief review of the pertinent properties of chitosan that are relevant to biology, the design and critical evaluation of varied chitosan-based platforms is discussed. Future directions in exploiting important features of chitosan in this area can be derived from the presented comparative evaluation of the current literature in drug delivery.

Introduction

Chitosan, a semi-crystalline and linear biopolymer, is produced with chitin deacetylation, a structural compound in naturally occurring crustaceans such as crabs, shrimps, and some insects [1]. Chitin is an ingredient of the outer shell in crustaceans, which is employed to protect their inner soft organs from external damage, and help them gnaw wood or metal [2]. Scheme 1 below shows chemical conversion of chitin to chitosan via acetylation/deacetylation. Chitosan has several surface reactive groups (free amine and hydroxyl groups) [1] chemically bonded to its rigid N-acetyl glucosamine, and glucosamine units which are linked by 1,4-glycosidic bonds. It is a cheap, abundant, biocompatible, and biodegradable polysaccharide, which can interact with a diverse range of hydrophilic molecules by hydrogen bond formation or electrostatic interactions, and make complex structures with proteins and nucleic acids [3]. It has high affinity for cell membranes [4], bioadhesive functionality [5], and good transfection efficiency via avid complexation with negatively charged DNA and RNA [3,6,7]. Chitosan can also be used as a metal ion chelator [8]. All these properties originate from its protonated amine groups (positively charged content) in acidic conditions. These characteristics of chitosan and its intrinsic antimicrobial and cell-adhesive behavior mostly depend on the degree of deacetylation, crystallinity, modification, molecular weight, etc. [9].

Chitosan has been widely used for tissue engineering scaffolds, and for the formation of hydrogels, self-assembled micro/nanoparticles, as well as nanofibers [10] for targeted or systemic cargo release. Targeted delivery to the diseased or injured area without causing any side effects to healthy tissue is a new approach in biomedical engineering [[11], [12], [13]]. In addition to all the above-mentioned properties of chitosan, its behavior under physiological conditions yields an interesting platform in designing stimuli-responsive delivery devices. Any changes in the environmental pH alter its solubility in an aqueous medium [[14], [15], [16]] and affect its interactions with other compounds due to protonation (low pH) and deprotonation (high pH) of free amine groups [17,18]. In addition, chitosan can be associated with lysozyme and chitosanase to enzymatically degrade and convert to oligosaccharides and monosaccharides, and thus, facilitate drug release in the desired area [19].

One of the limitations in developing chitosan-based technology for biomedical applications is its solubility only in an acidic environment, and insolubility at neutral pH under extra- and intracellular conditions [19]. However, owing to several active groups such as hydroxyl and free amines, chitosan can be easily modified (Scheme 2) to facilitate its solubility at neutral pH in cellular microenvironments. This is crucial for sensitive cargo such as proteins, genes, and drugs that could potentially get denatured under acidic conditions. Surface functionalization of chitosan enhances controlled cargo delivery compared to naked chitosan, due to its modified electrostatic, hydrophobic, or hydrophilic interactions [20,21].

Due to disparity in the environment (pH, enzyme concentration, etc) around diseased or injured areas compared to healthy ones, stimuli-responsive materials for drug delivery have gained considerable attention recently [22,23]. There are two types of stimuli: (i) internal that include glutathione (GSH), reactive oxygen species (ROS), enzymes, pH, and temperature [24,25]; and (ii) external such as ultrasound, light, magnetic/electrical fields, and mechanical stimulus [[25], [26], [27]]. Among a variety of biomaterials that can respond to these stimuli, modified chitosan as a biocompatible polymer with specific functional groups, provides an advantageous platform, as its solubility, hydrophilicity, biodegradability and chemical behavior can be easily modified with respect to conditions of the biological environment. Functional groups (amines and hydroxyls) of chitosan have been physically or chemically linked to the pH [28], ROS [29], GSH [30], and thermo-responsive [31] moieties, to design stimuli-responsive hydrogels [[32], [33], [34]], micro- nanoparticles [[35], [36], [37], [38]], and self-assembled micelles [[39], [40], [41]] for cargo and intracellular delivery, tissue engineering, and other biomedical applications. The specific environmental stimulants at diseased sites can be used to initiate and/or control drug release. For example, physiological pH can vary from acidic in GI to neutral in endosomes and lysosomes. Modified chitosan can respond to these pH changes by swelling, shrinking, degrading, protonation and deprotonation of functional groups, and thus release encapsulated drug in a controlled manner [42,43]. In addition, functionalized chitosan can respond to the body temperature under normal and disease conditions (37 °C to 37.5–41 °C), due to changing hydrophilic and hydrophobic interactions between stimuli-responsive conjugated species and chitosan chains, below and above its lower critical solution temperature (LCST) [[44], [45], [46], [47]]. Another example of stimulus in the body is the high concentration of ROS in cancer cells, as well as at sites including neurological disorders, cardiovascular diseases, sensory impairments, inflammation, infectious and fibrotic diseases [48,49]. Chitosan has been modified with ROS-responsive moieties to increase controlled cargo delivery [29]. GSH is produced intracellularly and is required for cell life. However, in some diseases such as cancer, it can be increasingly generated in the cells from 2 to 10 mM concentrations. The enhanced concentration has been used as a stimulus for drug delivery by chemically linking molecules with disulfide bonds, and thus develop easily manipulated GSH-responsive structures [50]. Furthermore, enzymes play a remarkable role in most of the biochemical processes in the body, and any aberration in the expression of the enzymes (such as protease, phospholipase, or glycosidase) is associated with diseases such as cancer or inflammation [51,52]. Compared to other stimuli, enzyme-responsive systems benefit from both high sensitivity and precise selectivity in the enzyme-over-expressed tissues or cells [53,54]. To prepare desired amphiphilic biocarrier, enzyme-responsive moieties can be covalently or non-covalently linked to the polymers. Enzymes can convert the assembled amphiphilic biocarriers into disassembled structures so that the drug can be released [53]. Lastly, chemical concentration or electrical charge gradient around cells can also be a driving force for changing the conformations of modified chitosan and stimulate drug release [55]. External stimuli such as light, ultrasound, magnetic/electrical fields, and mechanical stimuli affect the conformation or configuration of chitosan in the diseased tissue. These stimuli can be applied to improve cargo release into the diseased area to treat cancer [32,56,57], heart attack [58], and neurodegenerative diseases including Alzheimer's and Parkinson [[59], [60], [61], [62]]. Fig. 1 represents a summary of recent research articles on stimuli-responsive chitosan based systems. The data used in this figure were extracted using a keyword-based data mining on the Scopus database for the time period 2009–2019. It is notable that pH-, thermo- and enzyme-responsive chitosan structures are the most widely investigated due to the presence of such stimuli inside the body under normal to diseased conditions.

The presence of various functional groups in chitosan facilitates its modification to develop stimuli-responsive structures for improved/controlled drug delivery [19]. Chitosan contains abundant hydroxyl and amine groups in its backbone which can covalently link to biomaterials, electrostatically interact with charged molecules, or physically interact (for example through hydrogen bonds) with a variety of hydrophilic/hydrophobic molecules. This interaction can also help overcome strong hydrogen bonds between its chains, and thus make it soluble at neutral pH. Consequently, physical modification or chemical functionalization of chitosan as a non-toxic biopolymer can make it an inimitable matrix to deliver bioactive agents. To improve chemical, physical, and mechanical properties of chitosan, a variety of anionic or neutral, natural and synthetic polymeric materials such as alginate, hyaluronic acid (HA), gelatin, polyacrylic acid (PAA), polyethylene glycol (PEG) have been employed, which can physically or chemically interact with chitosan [63]. Due to environmental concerns about chemical reagents for functionalization of chitosan, enzymatic grafting of chitosan has emerged as a non-toxic and environment-friendly method for its modification [19,64]. Aerogels consisting of carboxylated chitosan and hairy nanocellulose have been shown to have high adsorption capacity of cationic compounds depending on pH [65].

In this review, we will particularly focus on how chitosan as a biocarrier can respond to different external and internal stimuli for controlled drug delivery applications. Chitosan has been modified with a variety of stimuli-responsive structures which respond to the biological environment, and release their cargo in a controlled manner. Depending on the type of disease and the condition of damaged tissue, a typical stimuli-responsive chitosan structure needs to be utilized for maximum efficacy. For example, different amounts of ROS- and GSH-responsive units, or enzymes have been associated with releasing a specific quantity of bioactive agents, which is required during the period of treatment of the disease. To the best of our knowledge, other existing reviews on chitosan have focused particularly on its chemical modification, self-assembly, combinatorial approaches, [28,66,67], and a few on internal stimuli with a specific type of carrier such as nanotemplates [[68], [69], [70], [71], [72], [73]]. However, none of these have collectively reviewed stimuli-responsive chitosan structures (both internal and external), and their unique characteristics for cargo delivery.

Section snippets

pH-responsive chitosan

Developing pH-responsive drug-loaded carriers is of particular interest as pH gradients generally exist physiologically inside the body or along the GI [74,75]. Pathological sites such as ischemia [76], infections [77], inflammation [78], or cancerous tumor [79] have different pH profiles than the normal tissue. In tumor cells, the cancerous tissue has an extracellular pH of around 6–7, and this environment is mostly due to the high rate of their proliferation, which limits nutrition and oxygen

Electrical/magnetic-responsive chitosan

In recent years, bio-friendly artificial synapses with learning capabilities have attracted increasing attention as neuronal platforms. For example, chitosan-based polysaccharide-gated flexible indium-Tin oxide (ITO) synaptic transistors have been applied for learning abilities by mimicking neuronal synapsis. This electrically-responsive chitosan-based material showed good performance against mechanical stress and synaptic plasticity, and mimicked natural synapses in neural cells. The

Conclusions

Chitosan presents an interesting template to develop novel materials for biomedical applications. Its rich surface functional groups, hydroxyl and amine, provide easy access to chemically introduce desired entities which can respond to various stimuli in biological media, both in vitro and in vivo. Functional groups in chitosan can respond to physiological conditions after physical, chemical and enzymatic modifications. Functionalized chitosan has been widely investigated for biochemical

Future outlook

Despite a remarkable advance in the design and development of stimuli-responsive structures a number of issues in preventing or managing various diseases remain unresolved or require further improvements. For example, chitosan, a biocompatible, biodegradable, highly abundant, and easily accessible compound, can be modified to respond to either internal or external stimuli such as pH or temperature. However, it is unclear if either of these sources of stimuli is equally effective and under which

Acknowledgment

We would like to thank Natural Sciences and Engineering Research Council of Canada and the Quebec Center for Advanced Materials/The Center Québécois sur les matériaux fonctionnels (QCAM/CQMF) for support. We would also like to thank Ms. Evan Rizzel Gran for reading the review and providing constructive feedback.

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