Dual-stimuli-responsive drug release from interpenetrating polymer network-structured hydrogels of gelatin and dextran

doi:10.1016/S0168-3659(97)00247-2

Journal of Controlled Release

Volume 54, Issue 2, 31 July 1998, Pages 191-200

https://doi.org/10.1016/S0168-3659(97)00247-2 Get rights and content

Abstract

Interpenetrating polymer network (IPN)-structured hydrogels of gelatin (Gtn) and dextran (Dex) were prepared with lipid microspheres (LMs) as a drug microreservoir, and LM release from these hydrogels was examined in relation to their dual-stimuli-responsive degradation. A phase morphology in the IPN-structured hydrogels was varied with the preparation temperature, i.e. above or below the sol-gel transition temperature (T_trans) of Gtn. The IPN-structured hydrogel prepared below T_trans exhibited a specific degradation-controlled LM release behavior: LM release from the hydrogel in the presence of either α-chymotrypsin or dextranase alone was completely hindered, whereas LM release was observed in the presence of both enzymes. It is concluded that dual-stimuli-responsive drug release can be achieved by specific degradation of a particular IPN-structured hydrogel.

Introduction

Biodegradable polymers have been studied in the development of drug delivery systems. The use of biodegradable polymers in controlled drug delivery systems is desirable, since the devices will be degraded in a living body after their use 1, 2, 3. The majority of studies concerning biodegradable polymers have focused on water-insoluble polymers such as poly(lactic acid) and poly(glycolic acid) [4]. Recently, hydrogels have received much attention for the development of new applications concerned with the dosage form and drug release in response to biological and external stimuli 5, 6, 7. Hydrogels are conventionally prepared by cross-linking hydrophilic polymers, and are believed to exhibit good biocompatibility as well as high responsibility for external stimuli.

More effective drug therapies for complicated diseases may require polymeric materials, the functions of which are variable or switchable in response to many kinds of stimuli. Indeed, the diagnosis of patients suffering from some diseases is generally achieved by monitoring several physiological changes [8]. However, previously reported stimuli-responsive polymers are designed to release a drug in response to a single stimulus. Thus, the integration of some information in the living body is thought to be important in the design of intelligent drug delivery systems. Such multi-stimuli responsive functions will act as a fail-safe mechanism for guaranteed drug delivery for a given disease. It can be indispensable to prevent the disorder of drug delivery when complicated diseases are being suffered, because much more physiological changes will occur spontaneously at the same time.

From these perspectives, our recent studies have focused on dual-stimuli-responsive degradation of biodegradable hydrogels with an interpenetrating polymer network (IPN) 9, 10, 11, 12. The concept of dual-stimuli-responsive drug release is illustrated in Fig. 1. In our first study, the in vitro degradation of IPN-structured hydrogels consisting of N-methacryloyl-glycylglycylglycyl-terminated poly(ethylene glycol) and dextran (Dex) was examined using papain and dextranase 9, 10. Specific degradation in the presence of papain and dextranase was observed in the IPN-structured hydrogel with a particular composition of oligopeptide-PEG and Dex. This hydrogel was not degraded by one of the two enzymes. It is considered that the dual-stimuli-responsive degradation observed in the IPN-structured hydrogel is achieved by controlling the chain entanglements between the two biodegradable polymers.

Our second approach for dual-stimuli-responsive degradable hydrogels was performed by combining gelatin (Gtn) and Dex as the constituents of IPN-structured hydrogels 11, 12. Gtn–Dex systems have important applications in the food and photographic industries [13]. Their binary behavior in aqueous solutions is well known to exhibit a specific phase separation that is closely related to the sol-gel transition temperature (T_trans) of Gtn [13]. The IPN-structured hydrogels were prepared below or above the T_trans of Gtn, and their enzymatic degradability was examined. Dual-stimuli-responsive degradation was achieved in the IPN-structured hydrogels with Gtn and Dex networks that were prepared below T_trans having increased miscibility 11, 12. It is suggested that the achievement in dual-stimuli-responsive degradation of the Gtn–Dex hydrogels was closely related to the miscibility between Gtn and Dex networks.

Drug release from biodegradable polymers can usually be controlled by diffusion through a matrix or by degradation of the matrix [14]. In particular, surface-degradable polymers have received much attention as substrates for regulated drug release. However, hydrogels are not suitable for regulated release of low molecular weight- and water-soluble drugs. In order to avoid drug leakage, hyaluronic acid (HA) hydrogels with lipid microspheres (LMs) as a drug microreservoir were prepared and their degradation properties were examined [7]. The HA hydrogels were found to result in degradation-controlled LM release.

In order to achieve drug release from our designed IPN-structured hydrogels in response to their dual-stimuli-responsive degradation, IPN-structured hydrogels of Gtn and Dex were prepared with LMs as a drug microreservoir in this study. The IPN-structured hydrogels were prepared with LMs at different temperatures, and LM release from these IPN-structured hydrogels was examined in relation to dual-stimuli-responsive degradation.

Section snippets

Materials

All chemicals were analytical-grade commercial materials and were used without further purification. Dextran (Dex) (M̄n=400 000) was purchased from Tokyo Chemical Industry, Japan. α-Chymotrypsin (52 U/mg) and dextranase from penicillium sp. (12.9 U/mg) were purchased from Sigma (St. Louis, MO, USA). Gelatin (Gtn) was purchased from Wako (Osaka, Japan). The molecular weight of Gtn was determined to be 1.0×10⁵ using Eq. (1)[15]. $[η]=1.66×10^{−5} [M ̄_{n}]^{0.885}$ where [η] is an intrinsic viscosity. A

Preparation and characterization of IPN-structured hydrogels with LMs

The preparation of IPN-structured hydrogels consisting of Gtn and Dex by sequential cross-linking reactions has been reported previously 11, 12. Phase separation of these hydrogels is dominated by the temperature-dependent gelation phenomenon of Gtn. In this study, the T_trans of Gtn was determined to be 20°C. Thus, IPN-structured hydrogels were prepared with LMs below or above the T_trans of Gtn.

The preparation of a Dex network was carried out by photoirradiation either below (4°C) or above the T

Conclusion

IPN-structured hydrogels of Gtn and Dex were prepared with LMs as a model of a drug substrate exhibiting dual-stimuli-responsive drug release. The IPN-structured hydrogel prepared below the T_trans exhibited a specific degradation behavior, i.e., hydrogel degradation by either α-chymotrypsin or dextranase alone was completely hindered whereas the hydrogel was completely degraded in the presence of both enzymes. Regulated LM release in response to dual enzymes was achieved in the IPN-structured

Acknowledgements

The authors are grateful to Prof. Dr. Minoru Terano and Dr. Hideharu Mori, Japan Advanced Institute of Science and Technology, for their valuable suggestions and discussion throughout this study.

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Dual-stimuli-responsive drug release from interpenetrating polymer network-structured hydrogels of gelatin and dextran

Abstract

Introduction

Section snippets

Materials

Preparation and characterization of IPN-structured hydrogels with LMs

Conclusion

Acknowledgements

Adv. Drug Deliv. Rev.

J. Control. Release

Inflammation responsive degradation of crosslinked hyaluronic acid gels

J. Control. Release

Regulated release of drug microspheres from inflammation responsive degradable matrices of crosslinked hyaluronic acid

J. Control. Release

Double stimuli-responsive degradable hydrogels for drug delivery: Interpenetrating polymer networks composed of oligopeptide-terminated poly(ethylene glycol) and dextran

Macromol. Rapid Commun.