Surface modifications and molecular imprinting of polymers in medical and pharmaceutical...

Journal of Controlled Release 72 (2001) 25–33www.elsevier.com/ locate / jconrel

Surface modifications and molecular imprinting of polymers inmedical and pharmaceutical applications

*Petr Bures, Yanbin Huang, Ebru Oral, Nicholas A. PeppasProgram on Therapeutic and Diagnostic Devices, Biomaterials and Drug Delivery Laboratories, School of Chemical Engineering,

Purdue University, 1283 Chemical Engineering Building (CHME), West Lafayette, IN 47907-1283, USA

Received 12 April 2000; accepted 2 October 2000

Abstract

Recent developments in the field of biomaterials are based on molecular design of polymers with improved surface andbulk properties. Novel techniques of surface modification by addition of tethered chains can lead to materials with the abilityto recognize biological and pharmaceutical compounds. Methods based on molecular imprinting can increase the recognitioncapabilities of such systems. Chain tethering can also can improve the mucoadhesive behavior of a delivery device and theeffectiveness of a drug by allowing targeting and localization of a drug at a specific site. Acrylic-based hydrogels arewell-suited for mucoadhesion due to their flexibility and nonabrasive characteristics which reduce damage-causing attritionto the tissues in contact. However, the adhesive and drug delivery capabilities of these devices can continue to be improvedas presently known bioadhesive materials are modified and more bioadhesive materials are discovered. Tethering of longPEG chains on PAA hydrogels and their copolymers can be achieved by grafting reactions involving thionyl chloride,followed by PEG grafting. The ensuing materials exhibit mucoadhesive properties due to enhanced anchoring of the chainswith the mucosa. Theoretical calculations can lead to optimization of the tethered structure. 2001 Elsevier Science B.V.All rights reserved.

Keywords: Molecular imprinting; Hydrogels; Molecular recognition; Tethered chains; Mucoadhesion

1. Introduction have shown that a number of these hydrogel carriersare mucoadhesive and can be used for protein

The utilization of hydrogels as carriers for protein delivery. We have also reported that various forms ofdelivery has been a subject of significant recent adhesive hydrogels based on poly(acrylic acid)research. In our recent work, we have shown that (PAA) or poly(methacrylic acid) (PMAA) exhibit andiffusion controlled delivery of proteins from hydro- unusual property of inhibition of the degradation ofgels containing poly(ethylene glycol) (PEG) is pos- various peptides and proteins (including insulin) bysible and can be controlled by the three-dimensional proteolytic enzymes.structure. Promising new studies from our laboratory Understanding of PEG-containing carrier /mucosal

adhesion is of utmost importance in local proteindelivery, especially in the upper small intestine. An*Corresponding author. Tel.: 11-765-494-7944; fax: 11-765-important contributor to good adhesion is the pres-494-0805.

E-mail address: [email protected] (N.A. Peppas). ence of molecular adhesion promoters such as poly-

0168-3659/01/$ – see front matter 2001 Elsevier Science B.V. All rights reserved.PI I : S0168-3659( 01 )00259-0

26 P. Bures et al. / Journal of Controlled Release 72 (2001) 25 –33

mer-tethered structures (e.g. PEG chains grafted to requirements of mucoadhesive hydrogels is still verycrosslinked networks) or even linear chains which limited [3]. A number of theories have been pro-are free to diffuse across the gel /gel interface. The posed to explain the experimental observations ofidea of using adhesion promoters to achieve im- mucoadhesion. A detailed description of theseproved bioadhesion is relatively new and was first models which include the adsorption, wetting, frac-proposed in our laboratory [1]. Tethering of polymer ture and interpenetration theories have been dis-structures can be accomplished either solely on the cussed in several excellent reviews [4,5]. No singlesurface of the hydrogel or in the bulk of the polymer theory can account for all the experimental observa-network. While surface tethering, i.e. grafting of PEG tions. Therefore, the actual mechanism of mucoadhe-chains on the surface of a hydrogel, would affect sion most likely involves a combination of thesemainly the bioadhesion of the carrier, tethering of theories. Even though there is a lack of completePEG on the polymer chains inside of the polymer theoretical understanding of the mechanism ofnetwork would primarily affect the bulk properties of mucoadhesion, experts in the field generally believethe carrier. that today’s mucoadhesive should be composed of a

PEG-containing multifunctional methacrylates are high molecular weight polymer that swells to a largeused as systems for molecular imprinting. This degree and is capable of forming multiple hydrogentechnique is used in producing synthetic polymers bonds [3].that are complementary in shape and function to a Hydrogels based on PAA, hyaluronic acid anddesired template molecule. Therefore, molecularly high molecular weight chitosans exhibit the aboveimprinted polymers (MIPs) have specific recognition mentioned properties. Among these, hydrogels basedcapability and binding affinity for that particular on crosslinked PAA have been the most heavilymolecule over structurally similar ones. The tech- investigated mucoadhesive candidates during the pastnique is a potential tool for designing systems that two decades. They also possess other properties,can be targeted toward undesirable compounds in the such as the ability to form hydrogen-bonding com-body or specific cells and tissues. plexes.

PEG star polymer gels have also been prepared by Mucoadhesive polymers have been shown to offergamma-irradiation and have been used for protein several advantages in addition to prolonged contactdelivery with or without molecular imprinting. PEG with the mucus of the target area. It is known thatstar polymers are three dimensional structures in lumenal degradation of proteins and peptides, causedwhich linear arms of the same or different molecular by gastrointestinal enzymes such as trypsin [6],weights emanate from a central core. The existence results in an extremely low bioavailability. However,of a large number of functional groups in a small Lueßen et al. [7] have shown that various grades ofvolume make these polymers important for use in PAA hydrogels are able to inhibit the hydrolyticbiological and pharmaceutical applications. These activity of trypsin using N-a-benzoyl-L-arginine-polymers provide micro- or nanoparticulate carriers ethylester as a model substrate. In further studiesfor drug delivery systems. they proposed and experimentally verified that the

underlying mechanism of the irreversible inhibitionof trypsin activity is associated with their ability to

21 212. Hydrogels with bulk tethered structures bind bivalent cations, specifically Ca and Zn ,which act as co-factors to the lumenal enzymes [8].

Bioadhesion addresses bond formation either be- Bai et al. [9] determined the ability of severaltween two biological surfaces or between synthetic grades of PAA hydrogels to inhibit degradation ofand biological surfaces [2]. Many soft tissues are calcitonin, insulin-like growth factor-I, and insulincovered by a viscoelastic gel of mucus whose main by colonic lumenal contents. They found that allfunction is to lubricate and protect the tissue cells grades of PAA were able to protect the proteins fromfrom microbial, chemical and mechanical damage. degradation and that this inhibition was dependent on

Despite the extensive research efforts in the area, the polymer concentration. At 0.1 w/v% concen-understanding of the mechanisms and structural tration of the polymer, only modest inhibition of the

P. Bures et al. / Journal of Controlled Release 72 (2001) 25 –33 27

degradation was observed. However, at 0.4 w/v% environmental pH on the network structure and thepolymer concentration, the PAA gels were able to protein drug release characteristics were studied. Theinhibit at least 90%, and in some cases, 100% of the average network mesh was three to 20 times larger inproteins’ degradation. Identical studies performed gels swollen in neutral or basic media than in acidicwith protease inhibitors and bile salts revealed that solutions in which complexation occurred. Thesuch additives, commonly added to drug release largest changes in network structure were observedformulations to protect them from enzymatic degra- in gels containing nearly equimolar amounts ofdation, have much weaker inhibitory effects than the methacrylic acid and ethylene glycol. Drug diffusionPAA gels. coefficients, determined through solute release ex-

Thus, PAA matrices have the ability to improve an periments, varied by two-orders of magnitude be-in situ colonic absorption of insulin. These encourag- tween the uncomplexed and complexed states.ing results were attributed to not only the increasedcontact time of these mucoadhesive polymers withthe gut wall, but also to the PAA’s ability to acidify 3. Tethered polymers on gel surfacesthe lumenal environment.

Our laboratory has been on the forefront of Gel surfaces can be molecularly designed forbioadhesive drug delivery through extensive research specific applications, and one way to achieve bioac-work on PAA and PMAA-containing hydrogels. Our tive surface is the using of tethered polymers [10].efforts have resulted in the development of copoly- One successful example is the incorporation ofmer networks of PAA grafted with PEG which RGD-containing tethered polymers in the PEG gelsexhibit pH-dependent swelling behavior due to the in order to introduce specific cell /hydrogel inter-reversible formation /dissociation of interpolymer action [11]. The generalized tethered polymer modi-complexes. These gels exhibit pH dependent swell- fied gel surfaces can be shown in Fig. 1. Theing behavior due to the presence of acidic pendant bioactive groups are connected to the gel surfacesgroups and the formation of interpolymer complexes through spacer chain blocks. Other used bioactivebetween the ether groups on the graft chains and groups include heparin and fibrinolytic enzymes forprotonated pendant groups. In these covalently cross- antithrombogenicity.linked, complexing hydrogels, complexation results The ability to specifically interact with differentin the formation of temporary physical crosslinks due protein /cell / tissues should the common desirableto hydrogen bonding between the PEG grafts and the property of most biomaterials. This can be achievedPMAA pendant groups. The physical crosslinks are by using designed polymers [12], which have molec-reversible in nature and dependent on the pH and ular recognition ability and hence specifically inter-ionic strength of the environment. Thus, the numberof crosslinks, both chemical and physical, the effec-tive molecular weight of the polymer chains betweenthese crosslinks and the end-to-end distance of thepolymer chains between these crosslinks or meshsize are strongly dependent on the pH and ionicstrength of the surrounding environment. In acidicmedia, such systems are relatively unswollen due tothe formation of the intermacromolecular complexes.In basic solutions, the pendant groups ionize and thecomplexes dissociate.

Because of the complexation /decomplexation phe-nomena, these gels exhibit large changes in their

Fig. 1. The schematic representation of tethered polymer modifiedstructure and are able to deliver proteins at varying hydrogel surfaces. The polymer chains have one end covalentlyrates depending on the pH of the environmental bound to the gel surfaces and have bioactive groups on the otherfluid. The effects of copolymer composition and the end.


act with biomolecules on different cell / tissue sur- Molecular modeling of tethered polymers on gelfaces. Tethering these designed polymers on general surfaces provides understanding of the structure /biomaterials render the latter biospecific interactions, performance relations in gel surface structureswhich is important for such applications as site- [10,16]. Although tethered chains on solid surfacesspecific drug targeting. are relatively well understood after two decades of

Tethered polymers on hydrogel surface (especially theoretical and experimental works [17], the study ofgel micro- or nano-particles) can also be used to tethered polymer /gel system is still at its beginning.induce lipid bilayer formation on surfaces, and the The major difference between a gel and a solid asresult is a ‘lipogel’, a hydrogel anchored lipid vesicle tethering substrates is that the former is penetrablesystem [13,14]. As shown in Fig. 2, these cell-mimic and deformable, which brings extra structure com-particles combine the properties of liposomes and plexities.hydrogels, both of which are widely used in bioap- The important parameters determining the tetheredplications, especially in drug delivery systems. More- surface structures include: (i) the gel polymer vol-over, the combination introduces more interesting ume fraction, (ii) the interactions between gel andproperties, such as the pore formation of the bilayer tethered polymers, (iii) the surface coverage and thecaused by the gel swelling transitions, and the chain length of tethered polymers, and (iv) thepossible self-healing of bilayer. These new properties interactions between tethered polymers and environ-are of great potential bioapplications and can also be ment solvents. A detailed theoretical investigationused as cell model systems [15]. can be found elsewhere [16]. We will use an example

The main advantages of surface-tethered polymers to show that the use of bimodal tethered chains caninclude: (i) the versatility of chemical and physical give novel surface properties of hydrogels.structures of tethered polymers, and (ii) the freedom For tethered layers consisting of two types ofto optimize separately the bulk structure of bioma- chains, if the surface total surface coverage is so lowterials. This two-step method provides a general way that the tethered chains hardly feel the effect ofto design most biomaterials. others, the two types of chains will behave in-

Fig. 2. ‘Lipogel’: a hydrogel particle anchored lipid vesicle system (adapted from Ref. [15]).


dependently. This condition becomes more complexwhen the interactions between the two types ofchains have a significant effect on the tetheredstructures, i.e. the total surface coverage becomeshigh enough [18,19].

We examine an example of a tethered layer whichis made of two types of chains. Short chains, S, are20-segment long, while long chains, L, contain 40-segment. They have different interactions with thebase gel but do not interact with each other.

The mixed tethered layer model can be used as: (i)an advanced approach to modify the gel surfaceproperties; and (ii) a more realistic model for gelsurfaces since gel surfaces usually have short dangl-ing chains before longer chains are grafted on.

In this example calculation, the volume fraction ofthe base gel is 0.3. The total surface coverage,s50.1, where the coverage is defined as the numberof tethered chains per unit surface area.

Fig. 3a and b show the segment distribution ofshort and long tethered chains in different com-position ratios in the mixed tethered layer. Both ofthese types of chains are repulsive to the base gelpolymers. As the composition of long chains de-creases with the total surface coverage fixed, thelong chains become more distorted and tend to havemore segments outside the layer of short chains. Atsome suitable composition, the outmost surfaceproperties of the gel are dominated by the longchains even though their fraction in the mixedtethered structures is low.

However, if the long chains are attracted to thebase gel while the short chains are not, the longerchains are mainly inside the base gel, and theoutmost surface properties are dominated by theshort chains. The change in the interactions between

Fig. 3. (a) The segmental distribution profiles of short chains in the grafted chains and the base gel can be induced bythe mixed tethered layer for three cases. The total surface environmental changes which in turn affect either thecoverage is 0.1, while the surface coverage ratio between short

tethered or gel chains. Fig. 3c demonstrates this forand long chains are 0.01 /0.09 (curve a), 0.05 /0.05 (curve b), andthe case when short chains are attracted to the0.09/0.01 (curve c), respectively. (b) The segmental distribution

profiles of long chains in the mixed tethered layer for three cases. surface while the long chains are not. The surfaceThe total surface coverage is 0.1, while the surface coverage ratio structure changes are sketched in Fig. 4.between short and long chains are 0.01 /0.09 (curve a), 0.05 /0.05(curve b), and 0.09/0.01 (curve c), respectively. (c) The segmentaldistribution of the short (curve a) and long (curve b) chains in thetethered layer as a function of the distance from the tethered 4. Molecular imprinting and applications in thesurface. The total surface coverage is 0.1, while the surface pharmaceutical fieldcoverages for the short and long chains are 0.09 and 0.01,respectively. The short chains are repulsive to the base gel but thelong chains are attractive to it. The objective of producing drug delivery systems


Fig. 4. The change of interaction between gel and long chain polymers changed the outmost surface properties of gels. The data are shownin Fig. 3.

targeted to specific sites and tissues has also necessi- Although the preparation of these systems istated the creation of systems with highly specific relatively simple, the quantity of the factors involvedrecognition capabilities. Molecular imprinting [20– makes the design quite complicated.22] is a powerful technique that is used in creating The most crucial step of the process is thesynthetic polymers with high selectivity for small optimization of the strength of interactions betweenmolecules. The technique involves polymerization the template and solvent and between template andaround the template of interest. The interactions functional monomers. The template should be com-between functional monomers and the template patible with the solvent so that it is soluble over amolecule are formed by non-covalent [23] or co- range of compositions, however, it should prefer tovalent bonds [24]. Upon polymerization, the template interact with the monomers over the solvent. Other-molecule and excess monomer are extracted from the wise, the solvent interferes with the formation of thesystem and what remains is a polymer that is desired specific interactions. High specificity is com-complementary to the template molecule functionally mensurate with the stability of the interactions(Fig. 5). between template and monomers during polymeri-

Each of the constituents of the molecular imprint- zation.ing system plays an integral and crucial role in the The preparation and use of MIPs in aqueousperformance of the system. The monomers termed solutions has been limited due to the fact that waterthe ‘functional monomers’ are responsible for the strongly interferes with the system [22,26]. Oneinteractions of the desired template with the poly- approach to overcoming this difficulty is the use ofmeric system. The interactions during polymerization organic solvents. However, the toxicity and incom-should be stable to ensure selectivity and affinity of patibility of these solvents limit the use of thesethe system for the template. The crosslinking ratio, polymers to sensors and separation equipment. Thetherefore, the crosslinking agent, is responsible for other approach is to use interactions between tem-providing the rigidity of the polymeric system and plate and functional monomers that are enhanced inthe intactness of the specific cavities for template water such as hydrophobic and metal coordinationbinding [25]. The solvent is a crucial component, interactions [27]. By this way, these systems resem-aiding in dissolving the other constituents and ac- ble the efficient systems of natural macromoleculescommodating the interactions of the template with and their ligands, whose interactions are dominatedthe functional monomer. Also, the amount of solvent by hydrophobic and in many cases metal coordina-during polymerization determines the overall po- tion interactions.rosity and the diffusional characteristics of the Although MIPs have largely been used to improvestructure. separation processes of structurally similar com-


Fig. 5. Molecular imprinting. The template and the functional monomers are allowed to interact. With the addition of a crosslinking agentand a solvent, polymerization proceeds around the template. Upon the extraction of the template with an appropriate solvent, the molecularlyimprinted polymer remains with a complementary binding site.

pounds and have shown great potential as biosensors recognition processes and to be able to predict and[28], and enzyme mimics [29,30], there are many quantify the performance of these systems.more applications where they find use as the more is Methacrylic monomers are used because of theirrevealed about the recognition mechanisms [31,32]. great versatility in providing different interactions.If used in drug delivery, systems can be created in PEG is incorporated into the systems as a com-which functions such as targeting, adhesion, and ponent, which can not only act as a functionalresponsive delivery can be accomplished (Fig. 6). monomer but also as a component providing lowThis can be done by creating specificity to com- immunogenicity. Glucose and theophylline are tem-pounds on cell or tissue surfaces. Surface imprinting plate molecules that are used as model systems. Thecan result in patterned surfaces that can be used for incorporation of glucose can aid in the use of thesecell separation. From another point of view, excess polymeric systems in responsive drug delivery foror toxic compounds can be extracted from the blood diabetes treatment.or body fluids with the use of MIPs. Our work [33] has also focused on the properties

Our research focuses on producing MIPs with of star polymer hydrogels as suitable systems fordifferent functional monomers that can provide ionic, molecular imprinting. Star polymers have the advan-metal coordination, hydrophilic and hydrophobic tage of high concentration of functional sites in ainteractions. The goal is to observe the effects of small volume. These properties can provide moredifferent types of interaction, solvents and templates stable interactions and it can also improve the lowon selectivity in order to understand more about capacity of MIPs.


Fig. 6. Example of target action in biological systems with MIPs. Using the molecular imprinting technique, undesirable compounds can beremoved from blood and other body fluids. Different constituents in the system can provide functions such as adhesion and degradation. (a)The polymer reaches the desired site and adheres to the surface by the adhesive layer. (b) The molecularly imprinted side captures theundesirable compound. (c) The linkages holding the polymer at the specific site degrade over time. (d) The polymer moves with the fluidbecause the linkages holding it on the surface are totally degraded.

5. Conclusions Acknowledgements

Recent advances in the fields of tethered polymers This work was supported by grants from theand molecular imprinting networks provide oppor- National Science Foundation (Grant No. BES-97-tunity to design novel intelligent systems for medical 06538) and the National Institutes of Health (Grantsand pharmaceutical applications. We examined the Nos. GM-43337-09 and GM-56231-01).use of tethered polymers in gel systems to make newdrug delivery carriers, and we discussed the designof molecularly imprinted gels for various medical Referencesapplications. We have used a molecular theory tocalculate of the structure of polymer layers tethered [1] J.J. Sahlin, N.A. Peppas, An investigation of polymer

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