Elsevier

Biomaterials

Volume 32, Issue 26, September 2011, Pages 6316-6323
Biomaterials

Carbon nanotube nanoreservior for controlled release of anti-inflammatory dexamethasone

https://doi.org/10.1016/j.biomaterials.2011.05.020Get rights and content

Abstract

On demand release of anti-inflammatory drug or neurotropic factors have great promise for maintaining a stable chronic neural interface. Here we report the development of an electrically controlled drug release system based on conducting polymer and carbon nanotubes. Drug delivery research using carbon nanotubes (CNTs) has taken advantage of the ability of CNTs to load large amounts of drug molecules on their outer surface. However, the utility of the inner cavity of CNTs, which can increase the drug loading capacity, has not yet been explored. In this paper, the use of multi-wall CNTs as nanoreserviors for drug loading and controlled release is demonstrated. The CNTs are pretreated with acid sonication to open their ends and make their outer and inner surfaces more hydrophilic. When dispersed and sonicated in a solution containing the anti-inflammatory drug dexamethasone, experiments show that the pretreated CNTs are filled with the drug solution. To prevent the unwanted release of the drug, the open ends of the drug-filled CNTs are then sealed with polypyrrole (PPy) films formed through electropolymerization. The prepared electrode coating significantly reduced the electrode impedance, which is desired for neural recording and stimulation. More importantly, the coating can effectively store drug molecules and release the bioactive drug in a controlled manner using electrical stimulation. The dexamethasone released from the PPy/CNT film was able to reduce lipopolysaccharide induced microglia activation to the same degree as the added dexamethasone.

Introduction

Neural prostheses based on implantable microelectrodes have been widely studied to modify, restore, or bypass a damaged or diseased portion of the nervous system. However, the chronic application of these neural electrodes has been limited due to degradation of performance over time, possibly due to the neuronal loss and scar formation through inflammatory tissue reaction [1], [2]. In order to minimize or eliminate the undesirable tissue reaction, strategies such as delivering/releasing anti-inflammatory drugs or neurotrophic factors to the vicinity of the implant are being explored. Drug release systems based on conducting polymers have been extensively studied, as conducting polymers offer the possibility of drug administration through electrical stimulation [3], [4], [5], [6], [7]. Electrically controlled release has found many applications [8], and it is particularly attractive for implantable devices such as neural electrode arrays. For example, neural microelectrodes modified with polypyrrole (PPy) or poly(3, 4-ethylene dioxythiophene) (PEDOT) incorporating nerve growth factor (NGF) can effectively deliver NGF to initiate the differentiation of rat pheochromocytoma cells [9]. The anti-inflammatory drug dexamethasone (Dex) has also been shown to be electrically released from PPy and PEDOT to mitigate the inflammatory tissue response [4], [5]. More recently, it was reported that cochlear implant electrodes coated with PPy films incorporating neurotrophin-3 could be used to preserve spiral ganglion neurons through electrically triggered neurotrophin delivery [6]. However, the application of such systems has been limited due to some intrinsic technical barriers. For instance, the drug loading capacity of a conventional conducting polymer film is limited, and the amount of drug release per stimulation is neither steady nor sustainable.

In recent years, carbon nanotubes (CNTs) have attracted considerable attention for their applications in biomedical science and technology [10], [11], [12], [13]. It was reported that the functionalized CNTs displayed low toxicity and no immunogenicity [14], [15], because the functionalized CNTs are dispersible in water and compatible with biological fluids, and they can be excreted through the renal route [16]. As CNTs can be functionalized with different molecules, such as proteins, nucleic acids and drugs, various types of drug delivery or controlled release systems based on CNTs have been developed [17], [18]. However, in most of these systems, the substances to be delivered were attached to the CNT surface through covalent or noncovalent binding [19], [20], leaving the inner cavity unutilized. When the ends of CNTs are opened [21], [22], the inner volume of the tubes becomes accessible and can be filled with different drugs, ranging from small molecules to peptides and even proteins. Although early work has reported on the filling of CNTs with water [23], C-60 [24], polystyrene nanobeads [25] and nanoparticles [26], [27], investigations into using the inner CNT cavity to load bioactive drugs are still in an early stage. Among the different methods proposed for loading drug into CNTs [28], the most convenient way is to fill the CNTs using solutions, but the filling efficiency is greatly reduced by the surface tension of the liquid inside the CNT [29]. Likewise, another challenge in using CNTs for drug delivery involves preventing the loaded drug from leaking out of the opened ends of CNTs until a controlled release is required.

Recently, Ajima and coworkers [30], [31], [32] have reported on the incorporation of cisplatin inside single-wall carbon nanohorns. Another interesting work was reported by Ren and Pastorin [33], where the antitumor drug hexamethylmelamine was incorporated inside single- and double-wall CNTs. Drug release from the open ends of the tubes was prevented by sealing the CNT with adsorbed C-60, which can later be removed in CH2Cl2 for a more controlled release. While these studies illustrate some of the recent progress in this area, there are still many fundamental and practical issues regarding the controlled loading and release of drugs from CNTs which must be addressed to make this a viable and useful technology. In particular, improving the amount of drug released, increasing the stability/lifetime of the releasing films, utilizing the unique porosity of the CNTs for storage/release, and providing mechanistic insight into the drug release process are still key issues that need to be addressed in these systems.

Herein, we report the use of multi-wall CNTs as nanoreserviors for drug delivery. CNTs were sonicated in strong acids to break them into shorter tubes and open their ends. The pretreated hydrophilic CNTs were then filled with a Dex solution. To make CNT nanoreserviors, the drug-loaded CNTs were encapsulated in PPy films through electropolymerization. The drug loaded in the PPy/CNT composite film can be efficiently released upon electrical stimulation. The CNTs served as nanoreserviors of Dex, provided a higher drug loading capacity, and possessed a more linear and sustainable release profile than that of a conventional PPy film.

Section snippets

Materials

Pyrrole (98%) was purchased from Sigma–Aldrich, vacuum distilled and stored frozen. Dexamethasone (Dex) 21-phosphate disodium salt was purchased from Sigma–Aldrich. Two types of multi-wall CNTs were used in this work, CNTs a (CNTa, outer diameter 110–170 nm, inner diameter 3–8 nm, length 5–9 μm, purity > 90%) were purchased from Sigma–Aldrich, and CNTs b (CNTb, outer diameter 20–30 nm, inner diameter 5–10 nm, length 10–30 μm, purity > 95%) were purchased from Cheap Tubes Inc. (Brattleboro,

Acid sonication of the CNTs

In order to provide access to the CNT inner cavity, as shown in Scheme 1, the CNTs must have at least one end open. As synthesized CNTs will typically have closed ends, but depending on the harvesting process, the tubes may possess some open ends [36]. In order to more fully open the ends of the CNTs, two samples (CNTa, outer diameter 110–170 nm, inner diameter 3–8 nm; CNTb, outer diameter 20–30 nm, inner diameter 5–10 nm) were treated with acid (1:3 concentrated HNO3 and H2SO4) under

Conclusions

An enhanced electrically controlled drug release system based on conducting polymer PPy incorporated with CNT drug nanoreserviors was developed. The CNT drug nanoreserviors, composed of CNTs with Dex loaded in their inner cavity and PPy coatings that seal the ends of CNTs, can effectively load drug and release them in bioactive form under electrical stimulations. The incorporation of CNT drug nanoreserviors can not only significantly increase the amount of loaded and releasable drug of the

Acknowledgments

The project described was supported by the National Science Foundation Grant 0748001 and 0729869, National Institute of Health R01NS062019, the Department of Defense TATRC grant WB1XWH-07-1-0716 and DARPA MTO N66001-11-1-4014.

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