Environment-sensitive hydrogels for drug delivery

Abstract

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 biosensors as well as drug delivery systems. Light-sensitive, pressure-responsive and electro-sensitive hydrogels also have the potential to be used in drug delivery and bioseparation. While the concepts of these environment-sensitive hydrogels are sound, the practical applications require significant improvements in the hydrogel properties. The most significant weakness of all these external stimuli-sensitive hydrogels is that their response time is too slow. Thus, fast-acting hydrogels are necessary, and the easiest way of achieving that goal is to make thinner and smaller hydrogels. This usually makes the hydrogel systems too fragile and they do not have mechanical strength necessary in many applications. Environmentally sensitive hydrogels for drug delivery applications also require biocompatibility. Synthesis of new polymers and crosslinkers with more biocompatibility and better biodegradability would be essential for successful applications. Development of environmentally sensitive hydrogels with such properties is a formidable challenge. If the achievements of the past can be extrapolated into the future, however, it is highly likely that responsive hydrogels with a wide array of desirable properties can be made.

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.