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While the earlier research in drug delivery has been focused on development of drugs, present methodologies target development of the delivery device itself (1–3). Implantable drug delivery devices offer various advantages such as maintenance of therapeutic blood levels, improved patient compliance, and improved safety (4). Nanorobots capable of treatment, prophylaxis, and diagnosis represent the next generation of drug delivery devices (5,6). Carbon nanotubes have been developed to seek and destroy tumor cells (7). Recently, Martin et al. tailored the width of microfabricated nanochannels to solute size to control diffusion kinetics of macromolecules (8).
In this study, a nanoporous metal surface has been characterized for purpose of drug delivery. Drug loading into nanopores can be achieved using solutions, colloidal solutions, or polymer–drug systems. Early reports in literature have suggested use of lithography techniques for fabrication of nanostructures (9,10). Silicon wafers are coated with a combination of gold and silver. Gold is selected as a suitable surface material because it has been extensively used in development of novel nanodiagnostic tools due to its mechanical stability and biocompatibility (11–13). In photolithography, a photomask is used to transfer the pattern onto the wafer and a layer of photosensitive polymer (photo-resist) is applied using spin coating technique. The wafers are then exposed to ultraviolet light. The mask protects the portion of the wafer it covers, whereas the uncovered part gets etched by light. Silver, which is used as a sacrificial material, is precipitated out leaving, nanopores behind.
In the present study, standard metric techniques, namely scanning electron microscope (SEM) and atomic force microscope, were used for characterization of the nanopores. The dimensions of the nanopores were estimated, and the measurements were used to determine the total volume of pores available for drug loading. For purpose of estimation, a bare metal stent was used as a reference. Hence, the volume of nanopores if they were built on a stent surface was calculated.
In this study, nanopores were loaded using methyl orange, pH indicator (14). Poly (2-octyl cyanoacrylate) was used as a the polymer matrix because of its strong adhesive properties, biocompatibility, and as a drug carrier (15–17). It is also approved by FDA and is being currently used as a tissue adhesive (18). The role of the polymer here is to act as a sealing film formation to limit the rapid release of methyl orange from the nanopores.
Bare silicon wafers, gold-coated silicon wafers, and nanoporous gold-coated silicon wafers were obtained from Nanomedsystems, Charlottesville, VA, USA (formerly Setagon, Inc.). A bare metal stent (Palmaz-Schatz® Balloon-expandable stent, ) was obtained from The University of Texas Health Sciences Center, San Antonio, TX, USA. Methyl orange was obtained from Fisher Scientific. BAND-AID® Brand Liquid Bandage containing 2-octyl cyanoacrylate as the active ingredient was obtained from the local pharmacy store.
The bare metal stent’s length, width, and thickness were estimated using a Hitachi S-4500II SEM. Three wafers from each group of wafers were selected, and their surface morphology was compared using the SEM. Dimensional analysis of the nanoporous wafers was performed using SEM and AFM. The AFM topographic images of the nanoporous wafers were analyzed using the particle analysis and the section analysis commands, yielding length, width, area of the pores, and depth of the pores, respectively. The software used in AFM was Nanoscope 5.12b48 and the Cantilever used was of 300 kHz frequency.
A thin layer of an ethanolic solution of methyl orange was applied onto the surface, and ethanol was evaporated using a heat gun. A drop of 2-octyl cyanoacrylate solution was then applied onto the wafer followed by the addition of a drop of water for polymerization of the monomer. The weight of methyl orange and cyanoacrylate loaded was estimated gravimetrically by weighing the wafers after each step.
The in vitro drug release study in 10 ml of distilled water was performed in a non-stirred environment (19). After each 24-h period, aliquots were collected and replenished with fresh distilled water to assure sink conditions. The collected samples were retained for absorbance measurements at 464 nm against a blank.
The SEM pictures of the three distinct group of wafers, namely silicone wafer, gold-coated silicone wafer, and nanoporous gold coated silicone wafers, are illustrated in Fig. 1a–c, respectively. The length and width of nanopores can be measured manually from SEM pictures. The depth was estimated using AFM as illustrated in the topographic images (Fig. 2a, b). Table I represents the cumulative statistical data of the five nanoporous wafers. The SEM pictures (Fig. 1c) suggest the pores to be non-homogenous in shape. We assumed the majority of the pores to be cylindrical in shape. Hence the volume was estimated using the equation:
Where V, A, and D are the volume, area, and depth of the pores. Here, the pore area determined by the AFM studies is the area of the pore surface and not the area of the interior surface of the pore channel. The volume of nanopores was calculated as 3.55×104 nm3/μm2 area of wafer surface or 3.55×104 nm3/μm length of wafers.
A commercially available bare metal stent, which is made up of 87 mini cylindrical rods, was used for calculations (Fig. 3a). The length, width, and thickness of the rods were estimated using SEM pictures (Fig. 3b). The stent is cylindrical in shape with open ends. Figure 3b indicates the length of the cylindrical rods as 1.3×103 μm. Hence,
Hence, total volume of pores available on entire length of the stent can be given by:
The aim of this study was to characterize the drug loading capacity of nanopores. The drug loading data, which are summarized in Table II, indicates that a uniform w/w ratio of methyl orange and cyanoacrylate, 0.70±0.04, was applied to the wafers. The average cumulative percentage release of 88.1±5.0%, equivalent to 220±97 μg/day of methyl orange, was obtained for first 7 days (Fig. 4). Certain patients may be hypersensitive to polymers (20), in such cases, biodegradable or bioabasorbable polymers may be used instead of poly-cyanoacrylates.
Gold proved to be an effective material for the fabrication of nanopores, which can be fabricated in different patterns and by different techniques. SEM and AFM have proven to be useful tools in analyzing nanofeatures. Poly (2-octyl cyanoacrylate) can be successfully used to prolong methyl orange release from nanoporous surface, metals, and probably other surfaces. The technique can be extended to hydro- and lipophilic drugs. The result of this study suggests the possible use of nanoporous surfaces for extended drug release.
An erratum to this article can be found at http://dx.doi.org/10.1208/s12248-009-9161-9