Poly(ethylene glycol)-containing hydrogels in drug delivery

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Abstract

The use of hydrogels as carriers for protein delivery has been a subject of significant recent research. In our recent work, we have shown that diffusion controlled delivery of proteins from hydrogels containing poly(ethylene glycol) (PEG) can be possible and controlled by the three-dimensional structure. In addition, a number of these hydrogel carriers are mucoadhesive and can be used for protein delivery. PEG star polymer gels have also been prepared by gamma-irradiation and have been used for protein delivery with and without molecular imprinting. The presence of a large number of functional groups in a small volume makes these polymers important for use in biological and pharmaceutical applications. PEG star polymer hydrogels were synthesized using gamma-irradiation and were characterized using swelling techniques. Equilibrium swelling studies were conducted to investigate the effects of molecular weight, number of star arms, concentration, and radiation dose.

Introduction

Poly(ethylene glycol) (PEG) is a non-toxic, water soluble polymer which resists recognition by the immune system. The term PEG is often used to refer to polymer chains with molecular weights below 20 000, while poly(ethylene oxide) (PEO) refers to higher molecular weight polymers [1]. It exhibits rapid clearance from the body, and has been approved for a wide range of biomedical applications. Because of these properties, hydrogels prepared from PEG are excellent candidates as biomaterials. PEG may transfer its properties to another molecule when it is covalently bound to that molecule. This could result in toxic molecules becoming non-toxic or hydrophobic molecules becoming soluble when coupled to PEG [1].

Coupling of a biological molecule to PEG usually contributes to its biological activity. This renders PEG surfaces resistant to cell and protein adsorption [4]. Proteins that are tethered to PEG are not denatured and their rate of clearance through the body is often increased because their size is increased. Such properties make PEG-containing hydrogels excellent candidates as drug delivery systems [2].

An improved utilization of PEG is through star polymer structures. Star polymers are three-dimensional hyperbranched structures in which linear arms of the same or different molecular weight emanate from a central core. Star polymers may be used in a variety of biomedical and pharmaceutical applications because they provide a high density of functional groups in a small volume. This would result in star polymers that could act as drug delivery carriers [3]. PEG star polymers that terminate with a hydroxyl group can be prepared by the core-first anionic polymerization method which was developed by Rempp and colleagues [4], [5]. Typically, anionic polymerization produces a “living” core to which ethylene oxide can be polymerized. Another method of preparation has been reported by Yen and Merrill [6] to create PEG star molecules from dendrimer cores. This method produces well-characterized monodisperse star polymers, whereas the core-first anionic polymerization method produces highly polydisperse PEG star molecules.

PEG hydrogels are often prepared by radiation crosslinking of high molecular weight PEO or by chemical crosslinking by reaction of the hydroxyl groups on the ends of PEG. The radiation dose needed to crosslink PEG chains is dependent not only on the molecular weight, but also on the concentration of PEG in the solution [7]. Stringer and Peppas [8] and Kofinas et al. [9] have studied hydrogels prepared from aqueous solutions of linear PEO using irradiation. Merrill and Sofia [10] developed a two step procedure using electron beam irradiation to bind linear and star PEO to polymer surfaces. Merrill et al. [11] prepared PEG star polymer hydrogels using electron beam irradiation. These hydrogels have a larger number of free hydroxyl ends as compared to hydrogels prepared from linear PEG chains. Because crosslinking occurs randomly between PEG chains, a large number of hydroxyl groups are left available for biological reaction. Unfortunately, it is difficult to control the structure of these gels using radiation crosslinking techniques. Thus, rational design of PEG-containing gels requires exact chemical crosslinking or endlinking techniques

PEG hydrogels have been used in drug delivery, wound healing, and a variety of other biomedical applications [1], [3]. These hydrogels are often used in combination with other polymers to produce an appropriate biomaterial. PEG has formed a basis for some commercial products including Vigilon™ which is formed by radiation crosslinking of high molecular weight PEO chains. This product is used as a sheet wound covering materials. Hypol™ is a crosslinked PEG foam used in wound healing and drug delivery materials [7]. PEG hydrogels have been used as controlled release devices [12], [13], [14], [15], [16]. The rate of drug release was found to be dependent not only on the method of preparation, but also on the crosslinking density, molecular weight of the PEO chains, and drug solubility.

We have developed a new class of gels containing increased amounts of PEG. These materials can be prepared in a manner such that we can easily tailor the properties of the networks for a specific application. Here, we introduce a new method for producing highly crosslinked PEG-rich networks containing PEG bridges and PEG grafts with a structure shown in Fig. 1. In our recent work, we have shown that diffusion controlled delivery of proteins from such hydrogels containing poly(ethylene glycol) (PEG) can be possible and controlled by the three-dimensional structure [17]. Promising new studies from our laboratory, showed that a number of these hydrogel carriers are mucoadhesive and can be used for protein delivery [18], [19]. Understanding of PEG-containing carrier/mucosal adhesion is of utmost importance in local protein delivery, especially in the upper small intestine. An important contributor to good adhesion is the presence of molecular adhesion promoters such as polymer-tethered structures (e.g. poly(ethylene glycol) chains grafted to crosslinked networks) or even linear chains which are free to diffuse across the gel/gel interface. The idea of the use of adhesion promoters to achieve improved bioadhesion is relatively new and was first proposed in our laboratory [20], [21].

These ideas have led to the development of copolymer networks of poly(methacrylic acid) grafted with poly(ethylene glycol) which exhibit pH-dependent swelling behavior due to the reversible formation/dissociation of interpolymer complexes. In acidic media, such systems are relatively unswollen due to the formation of the intermacromolecular complexes. In basic solutions, the pendant groups ionize and the complexes dissociate. Because of complexation/decomplexation phenomena, these gels exhibit large changes in their structure and are able to deliver proteins at varying rates depending on the pH of the environmental fluid. Fig. 2 shows the general behavior of these gels, and indicate that the mesh size, ξ, expands and contracts due to hydrogen bonding complexation.

The effects of copolymer composition and the environmental pH on the network structure and the protein drug release characteristics have been studied [19]. The average network mesh was three to 20 times larger in gels swollen in neutral or basic media than in acidic solutions in which complexation occurred. Drug diffusion coefficients, determined through solute release experiments, varied by two-orders of magnitude between the uncomplexed and complexed states [22].

Section snippets

Preparation of PEG star polymer hydrogels

PEG star polymer gels were prepared using various molecular weights, number of star arms, concentrations, and radiation doses. PEG star polymers (Shearwater Polymers, Huntsville, AL) were dissolved in deionized water at concentrations of 10 or 20 wt%. The two grades of star polymers used were: star-PEG 423 (n=450 000; f=75), and star-PEG 432 (n=624 000; f=31), where f is the functionality, or the number of PEG arms, and n is the number average molecular weight of the sample. The solutions

Swelling behavior of PEG star gels

We investigated first the swelling behavior of PEG star hydrogels which were prepared for 20 wt% aqueous solutions of star-PEG 423 (n=450 000; f=75) and star-PEG 432 (n=624 000; f=31) using a gamma-irradiation dose of 10 Mrad. The gels were cut into disks and placed in deionized water at 37°C. The weight swelling ratio was calculated as a function of time. The weight swelling ratio increased and begun to level off in the first eight hours. After the first 8 h, the weight swelling ratio

Conclusions

PEG star polymer hydrogels were synthesized using gamma-irradiation and were characterized using swelling techniques. Equilibrium swelling studies were conducted to investigate the effects of molecular weight, number of star arms, concentration, and radiation dose. PEG-containing, acrylate-based networks were also prepared by random copolymerizations, and their swelling and release behavior were studied as functions of the crosslinking structure and the nature of the PEG acrylate studied.

We

Acknowledgements

This research contribution is dedicated to Professor Tsuneji Nagai on the occasion of his 65th birthday. This work was supported in part by grants for the Showalter Foundation and the National Institutes of Health (grant no. GM 56231)

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    Present address: Department of Chemical Engineering, Drexel University, Philadelphia, PA 19104, USA.

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