Subcompartmentalized Surface-Adhering Polymer Thin Films Toward Drug Delivery Applications Boon M

207 10 Subcompartmentalized Surface-Adhering Polymer Thin Films Toward Drug Delivery Applications Boon M. Teo, Martin E. Lynge, Leticia Hosta-Rigau, and Brigitte Städler 10.1 Introduction Integrating (bio)materials into living organisms heavily relies on the properties of the biointerface. Polymer coatings are successful tools to engineer this inter- face from protein repelling over selective cell adhesion to antimicrobial. Therefore, polymer thin films are essential building blocks for devices with applications rang- ing from tissue engineering to drug delivery [1]. There is a wide range of opportu- nities to modify different materials with polymer thin films including spray coating, dip coating, self-assembled monolayers, surface grafted or tethered polymer layers, as well as polymer multilayer assembly. The latter concept, the layer-by- layer (LbL) assembly technique, is among those approaches which have the inher- ent power to be successful due its simplicity, flexibility, and reproducibility [2]. Further, the LbL assembly method offers precise control over the composition and properties of the films depending on the chosen building blocks during assembly. Although LbL coatings can be deposited on virtually any substrate, the focus of this chapter is on planar substrates, and the film deposition/characterization and their applications are discussed in this context. LbL films consisting only of polymers can be employed to control cell adhesion and differentiation depending on the type of polymer, cross-linking density, terminating layer, and so on [3]. While the success of polymer coatings is an incon- trovertible fact, plain polymer films are insufficient to address many challenges. Embedding of active compounds, for example, proteins [4] or genes [5], toward substrate-mediated drug delivery (SMDD) is an approach to enhance the func- tionality of LbL coatings, but it is limited in the type and amount of compounds that can be trapped this way. It can be in particular challenging for small molecular payload or cargo relying on its 3D structure such as enzymes. To this end, trapping larger carriers as drug deposits into the polymer films is a more recent concept that combines two different building components into the same hybrid film. The power of these composite coatings comes from the preservation of the advantages of the individual building blocks, while there is an option to overcome their shortcom- ings. Particularly promising are assemblies that employ fundamentally different Layer-by-Layer Films for Biomedical Applications, First Edition. Edited by Catherine Picart, Frank Caruso, and Jean-Claude Voegel. © 2015 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2015 by Wiley-VCH Verlag GmbH & Co. KGaA. 208 10 Subcompartmentalized Surface-Adhering Polymer Thin Films Toward Drug Delivery Applications Micelle Cyclodextrin Liposome Scheme 10.1 Cyclodextrins, block copolymer micelles, and liposomes as embedded drug deposits within a LbL film toward the use in surface-mediated drug delivery. building blocks to polymers yielding subcompartmentalized multilayered films. Although alternative films, for example, hydrogel-based ones, have been equipped with drug deposits [6], LbL coatings are inherently suitable to be extended in this direction using the deposits as a building block during the sequential assembly. The aim of this book chapter is to review the progress in subcompartmentalized surface-adhering LbL films for SMDD (Scheme 10.1). We aim to provide an overview over the predominant subcompartments used, namely cyclodextrins (CDs), block copolymer micelles (BCMs), and liposomes. Further, we will discuss miscellaneous subunits with potential in SMDD. Each of the approaches will be reviewed in terms of their assembly followed by their characterization relevant in SMDD. We will highlight those composite coatings successfully used to deliver (active) compounds to adhering cells, and emphasize the few films, which have been tested in vivo. In doing so, we hope to present the progress and impact these subcompartmentalized coatings have made over the past years as well as their potential and remaining challenges for their application in SMDD. 10.2 Cyclodextrin (CD)-Containing LbL Films CDs are cyclic oligosaccharides with a unique cup-like morphology with a polar exterior and a hydrophobic interior [7]. The nature of CDs allows for the 10.2 Cyclodextrin (CD)-Containing LbL Films 209 encapsulation of small hydrophobic molecules in an inclusion complex while the exterior of the CD cups can be easily modified with various chemical groups. CDs have been used in pharmaceutical formulations due to their versatility, low toxicity, and potential to enhance therapeutic effects while reducing toxic side effects of drugs [8]. 10.2.1 Assembly For incorporation of drugs into LbL films, the ability of CDs to convert a small hydrophobic therapeutic into a charged or hydrogen-bonding species is a very promising feature. In fact, modified CDs have been used for multilayer incorporation of several drugs and model compounds toward a range of applications including drug delivery and sensing. One of the first examples of multilayered thin films composed of CDs was reported by Xia and colleagues [9] who constructed films of polystyrene sulfonate (PSS) and a stable host–guest complex CBr2which was generated from sono- β chemical treatment of a bolaamphiphile, stilbenoid compound SBr2,and -CDs. In another early work, Park et al. [10] reported on the chemospecific immobiliza- tion of polyplexes on surfaces that take advantage of the ability of CD molecules to form inclusion complexes with hydrophobic organic compounds. They used polyethylene imine (PEI) functionalized with β-CD to form DNA/PEI polyplexes. Subsequent experiments demonstrated that these CD-functionalized polyplexes bind specifically to gold surfaces modified to present bulky hydrophobic adamantine groups. In another study utilizing β-CD, Van der Heyden et al. [11] constructed polyelectrolyte multilayers (PEMs) using host–guest interactions between β-CDs and adamantyl-grafted chitosans (Chi). The stability of the films was due to multivalent complexation occurring at each step of the construction. They also showed that these films were reversibly responsive to solvent change. Inamorerecentwork,Damet al. [12] reported on the preparation of degradable polyrotaxanes (PRXs) multilayer films based on positively and negatively charged disulfide-containing α-CD-poly(ethylene glycol) (PEG) PRXs (Figure 10.1a (i)). Film construction and degradation were monitored and film degradation was demonstrated upon exposure to reducing conditions, that is, glutathione (GSH) (Figure 10.1a (ii)). Although the work published by Xia, Park, Van der Heyden, and Dam was not evaluated in a biological context, they provided a framework for applications of this approach with potential in the context of drug delivery. 10.2.2 Drug Delivery Applications This section highlights recent reports describing PEMs with CDs for drug delivery applications including at least preliminary biological characterization. One of the first examples was reported by Jessel et al. [14] who demonstrated that it was possible to fabricate anti-inflammatory films by incorporating the 210 10 Subcompartmentalized Surface-Adhering Polymer Thin Films Toward Drug Delivery Applications (i) (ii) 1800 PEG 3 1600 1400 ) 1200 Capping Positive Negative Glutathione –2 1000 group Disulfide αCD αCD 800 600 2 / (ng cm 400 1 m 200 0 SiO surface SiO surface (a) 2 2 50 150 250 350 450 550 650 750 t /(min) (i) (ii) (iii) 100 Day 1 Day 3 Day 7 A A (poly1/PAA /GS/PAA) n 80 (poly1/PAA) 5 60 B (DMLPEI/PAA) 40 10 C 20 B COX enzyme inhibition (%) 0 (poly2/polyCD-DIC) M) D n μ No drug (DMLPEI/PAA) 10 Day 1 releaseDay 2 releaseDay 3 releaseDay 5 releaseDay 7 releaseDay 9 release (b) Carrier (polyCD) only Diclofenac only (44 Figure 10.1 (a) (i) Schematic diagram of PEM-containing PRX, showing the degradation of the films initiated by the reductive cleav- age of the PRX-capping groups. (ii) (PRX-DMEDA/PRX-Gly)4 multilayer formation and degradation initiated by the addition of GSH, as observed by optical waveguide lightmode spectroscopy. (b) (i) Schematic diagram of the combination films. (A) Gentamicin-releasing (poly1/PAA/GS/PAA)n and (B) diclofenac-releasing (poly2/polyCD-DIC)n combination films, built on top of the microbicidal (DMLPEI/PAA)10 films. (ii) Percentage of cyclooxygenase (COX) enzyme inhibition showing that diclofenac released from (DMLPEI/PAA)10(poly2/polyCD-DIC)10 is still active. (iii) Proliferation (days 1, 3, and 7) of MC3T3-E1 cells on (A) bare glass substrates and (B) (DMLPEI/PAA)10 films; proliferation of A549 cells on (C) bare glass substrates and (D) (DMLPEI/PAA)10. (Reproduced with permission from Ref. [13].) 10.2 Cyclodextrin (CD)-Containing LbL Films 211 drug piroxicam into PEMs through inclusion complexes using monomeric CDs. These films comprised of poly(L-lysine)(PLL) and poly(L-glutamic acid) (PGA) and up to three layers of CD-drug complexes. The drug release was monitored by suppression of the tumor necrosis factor alpha, an inflammatory cytokine, from stimulated monocytes. However, monomeric CDs were unable to properly trap small molecules, resulting in rapid drug release. The Hammond group [15] expanded on the initial work by using charged CD-polymers to stably trap drug molecules, ciprofloxacin, flurbiprofen, and diclofenac, showing that release kinetics were found to be independent of the therapeutic agent incorporated, and that the release kinetics could be regulated through

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