Environment-sensitive hydrogels for drug delivery
Introduction
Controlled drug delivery systems, which are intended to deliver drugs at predetermined rates for predefined periods of time, have been used to overcome the shortcomings of conventional drug formulations. Although significant progress has been made in the controlled drug delivery area, more advances are yet to be made for treating many clinical disorders, such as diabetes and rhythmic heart disorders. In these cases, the drug has to be delivered in response to fluctuating metabolic requirements or the presence of certain biomolecules in the body. In fact, it would be most desirable if the drugs could be administered in a manner that precisely matches physiological needs at proper times (temporal modulation) and/or at the proper site (site-specific targeting). In addition, the controlled drug delivery area needs further development of techniques for delivery of peptide and protein drugs. In the body, the appearance of numerous bioactive peptides is tightly controlled to maintain a normal metabolic balance via a feedback system called ‘homeostasis’ [1]. It would be highly beneficial if the active agents were delivered by a system that sensed the signal caused by disease, judged the magnitude of signal, and then acted to release the right amount of drug in response. Such a system would require coupling of the drug delivery rate with the physiological need by means of some feedback mechanism.
Hydrogels have been used extensively in the development of the smart drug delivery systems. A hydrogel is a network of hydrophilic polymers that can swell in water and hold a large amount of water while maintaining the structure. A three-dimensional network is formed by crosslinking polymer chains. Crosslinking can be provided by covalent bonds, hydrogen bonding, van der Waals interactions, or physical entanglements [2], [3]. Hydrogels can protect the drug from hostile environments, e.g. the presence of enzymes and low pH in the stomach. Hydrogels can also control drug release by changing the gel structure in response to environmental stimuli. Hydrogels containing such ‘sensor’ properties can undergo reversible volume phase transitions or gel–sol phase transitions upon only minute changes in the environmental condition. The types of environment-sensitive hydrogels are also called ‘Intelligent’ or ‘smart’ hydrogels [4]. Many physical and chemical stimuli have been applied to induce various responses of the smart hydrogel systems. The physical stimuli include temperature, electric fields, solvent composition, light, pressure, sound and magnetic fields, while the chemical or biochemical stimuli include pH, ions and specific molecular recognition events [5], [6]. Smart hydrogels have been used in diverse applications, such as in making artificial muscles [7], [8], [9], [10], [11], chemical valves [12], immobilization of enzymes and cells [13], [14], [15], [16], [17], [18], [19], [20], [21], and concentrating dilute solutions in bioseparation [22], [23], [24], [25], [26], [27]. Environment-sensitive hydrogels are ideal candidates for developing self-regulated drug delivery systems. For convenience, environment-sensitive hydrogels are classified based on the type of stimuli in this chapter.
Section snippets
Polymer structures
Temperature-sensitive hydrogels are probably the most commonly studied class of environmentally sensitive polymer systems in drug delivery research [28]. Many polymers exhibit a temperature-responsive phase transition property. The structures of some of those polymers are shown in Fig. 1. The common characteristic of temperature-sensitive polymers is the presence of hydrophobic groups, such as methyl, ethyl and propyl groups. Of the many temperature-sensitive polymers, poly(N
Polymer structures
All the pH-sensitive polymers contain pendant acidic (e.g. carboxylic and sulfonic acids) or basic (e.g. ammonium salts) groups that either accept or release protons in response to changes in environmental pH. The polymers with a large number of ionizable groups are known as polyelectrolytes. Fig. 4 shows structures of examples of anionic and cationic polyelectrolytes and their pH-dependent ionization. Poly(acrylic acid) (PAA) becomes ionized at high pH, while poly(N,N′-diethylaminoethyl
Glucose-sensitive hydrogels
One of the most challenging problems in controlled drug delivery area is the development of self-regulated (modulated) insulin delivery systems. Delivery of insulin is different from delivery of other drugs, since insulin has to be delivered in an exact amount at the exact time of need. Thus, self-regulated insulin delivery systems require the glucose sensing ability and an automatic shut-off mechanism. Many hydrogel systems have been developed for modulating insulin delivery, and all of them
Properties of electro-sensitive hydrogels
Electric current can also be used as an environmental signal to induce responses of hydrogels. Hydrogels sensitive to electric current are usually made of polyelectrolytes, as are pH-sensitive hydrogels. Electro-sensitive hydrogels undergo shrinking or swelling in the presence of an applied electric field. Sometimes, the hydrogels show swelling on one side and deswelling on the other side, resulting in bending of the hydrogels. The hydrogel shape change (including swelling, shrinking and
Properties of light-sensitive hydrogels
Light-sensitive hydrogels have potential applications in developing optical switches, display units, and opthalmic drug delivery devices. Since the light stimulus can be imposed instantly and delivered in specific amounts with high accuracy, light-sensitive hydrogels may possess special advantages over others. For example, the sensitivity of temperature-sensitive hydrogels is rate limited by thermal diffusion, while pH-sensitive hydrogels can be limited by hydrogen ion diffusion. The capacity
Other stimuli sensitive hydrogels
In addition to the widely used stimuli discussed above, other stimuli have also been used for making environmentally sensitive hydrogels. Other stimuli include pressure [112], specific ions [113], thrombin [114], [115], [116] and antigen [117].
Summary
Environmentally-sensitive hydrogels have enormous potential in various applications. Some environmental variables, such as low pH and elevated temperatures, are found in the body. For this reason, either pH-sensitive and/or temperature sensitive hydrogels can be used for site-specific controlled drug delivery. Hydrogels that are responsive to specific molecules, such as glucose or antigens, can be used as bisensors as well as drug delivery systems. Light-sensitive, pressure-responsive and
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