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AAPS J. Dec 2009; 11(4): 758–761.
Published online Oct 30, 2009. doi:  10.1208/s12248-009-9152-x
PMCID: PMC2782086
Characterization of Nanoporous Surfaces as Templates for Drug Delivery Devices
Ashish Rastogi, Tanushree Bose, Marc D. Feldman, Devang Patel, and Salomon Stavchanskycorresponding author
Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712 USA
Division of Cardiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229 USA
South Texas Veterans Affairs Health Care System, San Antonio, Texas 78229 USA
Salomon Stavchansky, Phone: +1-512-4711407, Fax: +1-512-4717474, stavchansky/at/mail.utexas.edu.
corresponding authorCorresponding author.
Received August 3, 2009; Accepted October 5, 2009.
Key words: cyanoacrylate, drug delivery, methyl orange, nanopores, volume calculation
While the earlier research in drug delivery has been focused on development of drugs, present methodologies target development of the delivery device itself (13). 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 (1113). 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 (1517). 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.
Materials
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, equation M1) 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.
Surface and Dimensional Analysis of Nanoporous Wafers
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.
Drug Loading of Nanoporous Wafers
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.
Drug Release Study
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.
Dimensional Analysis of Nanopores
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:
equation M2
1
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.
Fig. 1
Fig. 1
a Silicone wafer (magnification, ×500,000). The silicone serves as a start material for the production of nanopores. b The silicone wafer is coated with gold by dipping method (magnification, ×200,000). c Nanopores are produced on the (more ...)
Fig. 2
Fig. 2
The figure shows the nanopores as analyzed using AFM (a). The section analysis of 1-μm2 area of the wafer using AFM shows top view of the nanopores as indicated by the brown region and was used to analyze the depth of the pores (b). The particle (more ...)
Table I
Table I
Statistical Analysis of Nanoporous Wafers using Dimensions Obtained from AFM (N = 5)
Surface Analysis of a Stent and Estimation of Volume of Pores on Its Surface
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,
equation M3
3
Hence, total volume of pores available on entire length of the stent can be given by:
equation M4
Fig. 3
Fig. 3
a A skeleton design of a bare metal stent composed of 87 mini cylindrical rods. b SEM pictures of the stent were used to estimate the length of the cylindrical rods. The stent design and the reference stent were used as a reference to calculate the pore (more ...)
Drug Release Study
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.
Table II
Table II
Drug Loading Data (N = 3)
Fig. 4
Fig. 4
A cumulative percentage release profile of methyl orange from cyanoacrylate polymer matrix. Values are presented as mean with standard deviation (n = 3)
CONCLUSION
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.
Footnotes
An erratum to this article can be found at http://dx.doi.org/10.1208/s12248-009-9161-9
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