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Copyright copy 2010 American Scientific PublishersAll rights reservedPrinted in the United States of America

Journal ofNanoscience and Nanotechnology

Vol 10 345ndash348 2010

Drug Release Behavior from NanoporousAnodic Aluminum Oxide

Dae-Hyun Kwak Ji-Beom Yoo and Deug Joong Kimlowast

School of Advanced Materials Science and Engineering Sungkyunkwan University Suwon 440-746 Korea

In this study we developed a new drug delivery system using anodic oxidation The growth of aporous oxide layer on aluminum under anodic bias in various electrolytes has been studied for morethan 40 years Anodic Aluminum Oxide (AAO) has many uniform nanopores on its surface Thisnanoporous surface can be used for drug storage The effects of the diameter and depth of the AAOon the release characteristics of a drug were investigated Paclitaxel was used for the drug loadingand release test Paclitaxel was loaded on the inside of the AAO by ultrasonication The amount ofthe drug released from the AAO was analyzed by high performance liquid chromatography (HPLC)The pore size did not affect the drug release behavior However the depth of the pores had asignificant influence on the release rate of the drug

Keywords Nano Porous Materials Drug Release

1 INTRODUCTION

Several reports have shown that the baseline and proce-dural characteristics influence the risk of restenosis afterbare metal stent (BMS) implantation1ndash4 To solve this prob-lem drug eluting stents (DESs) were suggested RecentlyDESs such as sirolimus eluting and paclitaxel elutingstents have been proved to markedly reduce the incidenceof angiographic restenosis in selected patients56 In almostall cases it is possible to coat the DES with a polymerin which the antiproliferative drug is embedded Howeverit was found that the polymeric matrix on the stent mightinduce inflammation and thrombosis which is a seriouslimitation of this application7

Drug delivery from porous structures has attracted agreat deal of interest8 Anodic porous aluminum is one ofthe most attractive materials for use as a template withnanoporous structures for drug delivery applications910

The pore size and depth of AAO can easily be controlledby adjusting the anodizing voltage and time and the elec-trolyte composition11ndash13

A drug eluting stent made using AAO was reported byWieneke et al14 In our previous studies the feasibility ofusing AAO for drug eluting stents was investigated1516

In this case 2-deoxyadenosine was used as the drug forthe loading and release test However it was almost com-pletely released from the AAO in the incipient state of thein-vitro test due to its water-soluble properties Therefore

lowastAuthor to whom correspondence should be addressed

the effect of the pore structure on the drug release fromAAO was not clearly examinedIn this study Paclitaxel was used for the loading and

release test Paclitaxel is highly lipophilic and is essen-tially insoluble in water17 Since it inhibits cell prolifer-ation Paclitaxel is used as a mitotic inhibitor in cancerchemotherapy The effect of the pore structure on the drugrelease from the AAO was not discussed The control ofthe pore size and depth can change the loading space ofthe drug Our interest in the application of AAO to drugdelivery systems is focused on the effect of the pore sizeand depth of the AAO on the loading and release of thedrug The loading and release characteristics of AAO withvarious pore structures were examined and discussed

2 EXPERIMENTAL DETAILS

Pure aluminum (Al) foils (99999 wt) with a thicknessof 200 m were used in our experiment The Al foil in theform of a rectangular cut out (4 cmtimes1 cm) was used forthe fabrication of the AAO template Prior to anodizingthem the Al foils were electropolished in order to achievea smooth surface The electropolishing was performed ata constant current of 15 A below 25 C for 30 s in amixture solution consisting of HClO4 and C2H5OH at avolume ratio of 14 with magnetic stirring The polishedsample was then rinsed and air dried Two-step anodiza-tion was performed Two groups of samples were used toinvestigate the drug release behavior as a function of the

J Nanosci Nanotechnol 2010 Vol 10 No 1 1533-4880201010345004 doi101166jnn20101531 345

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RESEARCH

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Drug Release Behavior from Nanoporous Anodic Aluminum Oxide Kwak et al

Fig 1 Cross-section and top view ESEM images The secondary anodization was carried out in 03 M oxalic acid at 5 C at 40 V for 20 min andpore-widening was carried out for 30 min (a) Then TiO2 was deposited with a thickness of 5 nm (b) 10 nm (c) and 20 nm (d) The secondaryanodization was carried out in 01 M phosphoric acid at 30 C at 195 V for 60 min (e)

pore diameter and depth The first anodization was car-ried out at a constant voltage of 40 V in 03 M oxalicacid solution at 5 C for 1 hr after which the anodic filmswere removed in a phosphoric acid-chromic acid mixturesolution (CrO3H2PO4 = 186) at 60 C for 2 hrs The sec-ondary anodization was carried out in 03 M oxalic acidat 5 C at 40 V for 8 min 15 min 20 min or 90 min or in01 M phosphoric acid at 20 C at 195 V for 60 min afterwhich a pore widening process was carried out in 01 Mphosphoric acid at 30 C for 30 min or 60 min In the caseof several samples titanium oxide (TiO2) was depositedby Atomic Layer Deposition (ALD) in order to vary thepore size18

All of the samples were cleaned by means of a sono-smasher (Ulsoo Hi-Tech) for 20 min and then dried ina dry oven at 80 C for 24 hrs Then the AAO surfacewas treated with oxygen (O2) plasma in order to modifyit Paclitaxel (Samyang genex 99ndash100 C47H51NO14) andethanol were mixed at a ratio of 110 The AAO sheetsprepared using the different conditions were inserted intothe Paclitaxel solution and sonicated by the sonosmasherfor 2 hrs The sheet was then perfectly dried in a dryoven at 80 C for 24 hrs After putting the sample in10 cc of phosphate buffered saline (PBS) we performedthe release test every 24 hrs in an incubator at 365 CESEM (Environment Scanning Electron Microscopy) wasused to characterize the morphology of the AAO templateSamples of the released drug were analyzed by HPLC ona Phenomenex Gemini C-18 column (5 m 150 mmtimes460 mm) Chromatographic separation was achieved byusing a mobile phase consisting of methanol (Fisher co)

and DI-water (1090 vv for 10 min after 2080 vv) witha flow rate of 08 mlmin The UV detector was set at228 nm

3 RESULTS AND DISCUSSION

The pore structure of the AAO film is shown in Figure 1Hexagonal ordered domains can be seen all over the AAOsurface Figure 1(a) shows the top and cross sectionalimages of the specimen which was anodized in oxalic andphosphoric acid solution at a voltage of 40 V The pore

Fig 2 Top and cross-section view ESEM images before (a) and after(b) drug loading

346 J Nanosci Nanotechnol 10 345ndash348 2010

Delivered by Ingenta toSung Kyun Kwan University

IP 115145200154Fri 09 Apr 2010 054308

RESEARCH

ARTIC

LE

Kwak et al Drug Release Behavior from Nanoporous Anodic Aluminum Oxide

500

5

10

15

20

25

30

35

40

45

50 A

mou

nt [micro

g]

Time [hour]

pore size 20~30 nmpore size 40~50 nmpore size 50~60 nm standard 60~70 nmpore size 100~150 nm

450400350300250200150100

Fig 3 Cumulative paclitaxel release from the AAO films with variouspore diameters

diameter and depth of the specimen in Figure 1(a) are60ndash70 nm and 2 m respectively Figure 1(e) shows thetop and cross sectional images of the specimen which wasanodized in oxalic and phosphoric acid solution at a volt-age of 195 V The pore diameter and depth of the specimenin Figure 1(e) are 100ndash150 nm and 2 m respectivelyFigures 1(b) (c) and (d) correspond to the specimen

in Figure 1(a) on which TiO2 was deposited in order to

Fig 4 Cross-section and top view ESEM images The secondary anodization was carried out in 03 M oxalic acid at 5 C at 40 V for 8 min (a)15 min (b) and 20 min (c) The thicknesses of the oxide films were determined to be 500 nm 1 m and 4 m respectively

reduce the pore diameter by ALD Pore diameters of about50 40 and 20 nm were obtained after the deposition ofTiO2 for the specimens in Figures 1(b) (c) and (d) respec-tively All of the samples have a uniform pore depth of2 m Figure 2 shows a part of the AAO before andafter drug loading Empty nanopores can be seen beforedrug loading in Figure 2(a) However almost all of thepores were filled with the drug after loading as shown inFigure 2(b) Columns with a bent shape can be seen inthe cross section view (Fig 2(b)) which are consideredto be made up of the drug Figure 3 shows the plot of thecumulative drug release from the AAO films with differ-ent pore diameters Even after 400 hr the drug was stilleluted steadily The amounts of drug released from allof the specimens except for the one with a pore diam-eter of 20ndash30 nm were similar despite the difference inthe pore diameter This result means that the drug releaserate did not depend on the pore diameter The amountof drug released from the specimen with a pore diameterof 20ndash30 nm was larger than that from the other speci-mens However the drug release tendency except for theinitial release period of 120 hr was almost the same Itis believed that a large amount of the loaded drug waslocated on the surface of the specimen with a pore diam-eter of 20ndash30 nm after drug loading and was released inthe early stages

J Nanosci Nanotechnol 10 345ndash348 2010 347

Delivered by Ingenta toSung Kyun Kwan University

IP 115145200154Fri 09 Apr 2010 054308

RESEARCH

ARTIC

LE

Drug Release Behavior from Nanoporous Anodic Aluminum Oxide Kwak et al

00

5

10

15

20

25

Am

ount

[microg]

Time [hour]

500 nm 1 microm 4 microm

21619216814412096724824

Fig 5 Cumulative paclitaxel release from AAO films with various poredepths

In order to investigate the effect of the pore depth on thedrug release three different specimens with different thick-nesses were prepared First using oxalic acid at 5 C as anelectrolyte three identical AAO specimens were producedwith a pore diameter of 40ndash50 nm as shown in Figure 4Then three specimens with pore depths of 500 nm (a)1 m (b) and 4 m (c) were produced by controlling thesecondary anodization time Figure 5 shows the plot of thecumulative drug release from the AAO films with differ-ent pore depths Increasing the pore depth from 05 mto 4 m decreased the amount of drug released In thekinetics of drug release it is believed that the depth of thepores plays an important role as in the case of a diffu-sion controlled reaction When the drug release from thepores occurs through a diffusion controlled process therelease time is proportional to the square of the depthHowever the time-release curve showing the amount ofdrug released as a function of the pore depth in Figure 5did not correspond to that of a diffusion controlled reac-tion It is considered that the drug is released not onlyfrom the bottom but also from the side walls of the poresTherefore the mean diffusion distance may be smallerthan the pore depth

4 CONCLUSION

AAO films were fabricated using a two-step anodizing pro-cess that resulted in a highly uniform pore size and depthdistribution The pore diameter and depth of the AAO filmwere controlled by adjusting the applied voltage and sec-ond anodization time during the anodizing process and

ALD with TiO2 Paclitaxel was used for the drug load-ing and release test The amount of drug released did notdepend on the pore diameter However increasing the poredepth decreased the amount of drug released

Acknowledgment This study was supported by theKorea Science and Engineering Foundation (Grant NoR01-2004-000-10534-0)

References and Notes

1 A Kastrati A Schomig S Elezi H Schuumlhlen J DirschingerM Hadamitzky A Wehinger J Hausleiter H Walter and F JNeumann J Am Coll Cardiol 30 1428 (1997)

2 C Bauters E Huvbert A Prat K Bougrimi E V Belle E PMcFadden P Amouyel J M Lablanche and M Bertrand J AmColl Cardiol 31 1291 (1998)

3 N Mercado E boersma W Wijns B J Gersh C A MorilloV Valk G A van Es D E Grobbee and P W Serruys J AmColl Cardiol 38 645 (2001)

4 J Hausleiter A Kastrati J Mehilli H Schuumlhlen J Pache F DotzerJ Dirschinger and A Schoumlmig J Am Coll Cardiol 40 882 (2002)

5 M N Babapulle L Joseph P Belisle J M Brophy and M JEisenberg Lancet 362 583 (2004)

6 D G Katritsis E Karvouni and J P Ioannidis Am J Cardiol 95640 (2005)

7 W J van der Giessen A M Lincoff R S Schwartz M M vanBeusekom P W Serruys D R Holmes S G Ellis and E J TopolCirculation 94 1690 (1996)

8 Q ji M Miyahara J P Hill S Acharya A Vinu S B YoonJ S Yu K Sakamoto and K Ariga J Am Chem Soc 130 2376(2008)

9 M Saito M Kirihara T Taniguchi and M Miyagi Appl PhysLett 55 607 (1994)

10 D Routkevitch T Bigioni M Moiskovits and J M Xu J PhysChem 100 14037 (1996)

11 A P Li F Muller A Birner K Nielsch and U Gosele J ApplPhys 84 6023 (1998)

12 H El-Sayed S Singh M T Greiner and P Kruse Nano lett 62905 (2006)

13 F Zhang X H Liu C F Pan and J Zhu Nanotechnology 18345302 (2007)

14 H Wieneke O Dirsch T Sawitowski Y L Gu H BrauerU Dahman A Fischer S Wnendt and R Erbel Catheterizationand Cardiovasxular Interventions 60 399 (2003)

15 H J Kang D J Kim S J Park J B Yoo and Y S Ryu ThinSolid Film 515 5184 (2007)

16 H J Kang S J Park J B Yoo and D J Kim Solid State Phe-nomena 124ndash126 (2007)

17 J M Terwogt B Nuijen W W Ten Bokkel Huinink and J HBeijnen Cancer Treat Rev 23 87 (1997)

18 H Shin D K Jeong J Lee M M Sung and J Kim Adv Mater16 1197 (2004)

Received 30 August 2005 Accepted 5 November 2008

348 J Nanosci Nanotechnol 10 345ndash348 2010

Delivered by Ingenta toSung Kyun Kwan University

IP 115145200154Fri 09 Apr 2010 054308

RESEARCH

ARTIC

LE

Drug Release Behavior from Nanoporous Anodic Aluminum Oxide Kwak et al

Fig 1 Cross-section and top view ESEM images The secondary anodization was carried out in 03 M oxalic acid at 5 C at 40 V for 20 min andpore-widening was carried out for 30 min (a) Then TiO2 was deposited with a thickness of 5 nm (b) 10 nm (c) and 20 nm (d) The secondaryanodization was carried out in 01 M phosphoric acid at 30 C at 195 V for 60 min (e)

pore diameter and depth The first anodization was car-ried out at a constant voltage of 40 V in 03 M oxalicacid solution at 5 C for 1 hr after which the anodic filmswere removed in a phosphoric acid-chromic acid mixturesolution (CrO3H2PO4 = 186) at 60 C for 2 hrs The sec-ondary anodization was carried out in 03 M oxalic acidat 5 C at 40 V for 8 min 15 min 20 min or 90 min or in01 M phosphoric acid at 20 C at 195 V for 60 min afterwhich a pore widening process was carried out in 01 Mphosphoric acid at 30 C for 30 min or 60 min In the caseof several samples titanium oxide (TiO2) was depositedby Atomic Layer Deposition (ALD) in order to vary thepore size18

All of the samples were cleaned by means of a sono-smasher (Ulsoo Hi-Tech) for 20 min and then dried ina dry oven at 80 C for 24 hrs Then the AAO surfacewas treated with oxygen (O2) plasma in order to modifyit Paclitaxel (Samyang genex 99ndash100 C47H51NO14) andethanol were mixed at a ratio of 110 The AAO sheetsprepared using the different conditions were inserted intothe Paclitaxel solution and sonicated by the sonosmasherfor 2 hrs The sheet was then perfectly dried in a dryoven at 80 C for 24 hrs After putting the sample in10 cc of phosphate buffered saline (PBS) we performedthe release test every 24 hrs in an incubator at 365 CESEM (Environment Scanning Electron Microscopy) wasused to characterize the morphology of the AAO templateSamples of the released drug were analyzed by HPLC ona Phenomenex Gemini C-18 column (5 m 150 mmtimes460 mm) Chromatographic separation was achieved byusing a mobile phase consisting of methanol (Fisher co)

and DI-water (1090 vv for 10 min after 2080 vv) witha flow rate of 08 mlmin The UV detector was set at228 nm

3 RESULTS AND DISCUSSION

The pore structure of the AAO film is shown in Figure 1Hexagonal ordered domains can be seen all over the AAOsurface Figure 1(a) shows the top and cross sectionalimages of the specimen which was anodized in oxalic andphosphoric acid solution at a voltage of 40 V The pore

Fig 2 Top and cross-section view ESEM images before (a) and after(b) drug loading

346 J Nanosci Nanotechnol 10 345ndash348 2010

Delivered by Ingenta toSung Kyun Kwan University

IP 115145200154Fri 09 Apr 2010 054308

RESEARCH

ARTIC

LE

Kwak et al Drug Release Behavior from Nanoporous Anodic Aluminum Oxide

500

5

10

15

20

25

30

35

40

45

50 A

mou

nt [micro

g]

Time [hour]

pore size 20~30 nmpore size 40~50 nmpore size 50~60 nm standard 60~70 nmpore size 100~150 nm

450400350300250200150100

Fig 3 Cumulative paclitaxel release from the AAO films with variouspore diameters

diameter and depth of the specimen in Figure 1(a) are60ndash70 nm and 2 m respectively Figure 1(e) shows thetop and cross sectional images of the specimen which wasanodized in oxalic and phosphoric acid solution at a volt-age of 195 V The pore diameter and depth of the specimenin Figure 1(e) are 100ndash150 nm and 2 m respectivelyFigures 1(b) (c) and (d) correspond to the specimen

in Figure 1(a) on which TiO2 was deposited in order to

Fig 4 Cross-section and top view ESEM images The secondary anodization was carried out in 03 M oxalic acid at 5 C at 40 V for 8 min (a)15 min (b) and 20 min (c) The thicknesses of the oxide films were determined to be 500 nm 1 m and 4 m respectively

reduce the pore diameter by ALD Pore diameters of about50 40 and 20 nm were obtained after the deposition ofTiO2 for the specimens in Figures 1(b) (c) and (d) respec-tively All of the samples have a uniform pore depth of2 m Figure 2 shows a part of the AAO before andafter drug loading Empty nanopores can be seen beforedrug loading in Figure 2(a) However almost all of thepores were filled with the drug after loading as shown inFigure 2(b) Columns with a bent shape can be seen inthe cross section view (Fig 2(b)) which are consideredto be made up of the drug Figure 3 shows the plot of thecumulative drug release from the AAO films with differ-ent pore diameters Even after 400 hr the drug was stilleluted steadily The amounts of drug released from allof the specimens except for the one with a pore diam-eter of 20ndash30 nm were similar despite the difference inthe pore diameter This result means that the drug releaserate did not depend on the pore diameter The amountof drug released from the specimen with a pore diameterof 20ndash30 nm was larger than that from the other speci-mens However the drug release tendency except for theinitial release period of 120 hr was almost the same Itis believed that a large amount of the loaded drug waslocated on the surface of the specimen with a pore diam-eter of 20ndash30 nm after drug loading and was released inthe early stages

J Nanosci Nanotechnol 10 345ndash348 2010 347

Delivered by Ingenta toSung Kyun Kwan University

IP 115145200154Fri 09 Apr 2010 054308

RESEARCH

ARTIC

LE

Drug Release Behavior from Nanoporous Anodic Aluminum Oxide Kwak et al

00

5

10

15

20

25

Am

ount

[microg]

Time [hour]

500 nm 1 microm 4 microm

21619216814412096724824

Fig 5 Cumulative paclitaxel release from AAO films with various poredepths

In order to investigate the effect of the pore depth on thedrug release three different specimens with different thick-nesses were prepared First using oxalic acid at 5 C as anelectrolyte three identical AAO specimens were producedwith a pore diameter of 40ndash50 nm as shown in Figure 4Then three specimens with pore depths of 500 nm (a)1 m (b) and 4 m (c) were produced by controlling thesecondary anodization time Figure 5 shows the plot of thecumulative drug release from the AAO films with differ-ent pore depths Increasing the pore depth from 05 mto 4 m decreased the amount of drug released In thekinetics of drug release it is believed that the depth of thepores plays an important role as in the case of a diffu-sion controlled reaction When the drug release from thepores occurs through a diffusion controlled process therelease time is proportional to the square of the depthHowever the time-release curve showing the amount ofdrug released as a function of the pore depth in Figure 5did not correspond to that of a diffusion controlled reac-tion It is considered that the drug is released not onlyfrom the bottom but also from the side walls of the poresTherefore the mean diffusion distance may be smallerthan the pore depth

4 CONCLUSION

AAO films were fabricated using a two-step anodizing pro-cess that resulted in a highly uniform pore size and depthdistribution The pore diameter and depth of the AAO filmwere controlled by adjusting the applied voltage and sec-ond anodization time during the anodizing process and

ALD with TiO2 Paclitaxel was used for the drug load-ing and release test The amount of drug released did notdepend on the pore diameter However increasing the poredepth decreased the amount of drug released

Acknowledgment This study was supported by theKorea Science and Engineering Foundation (Grant NoR01-2004-000-10534-0)

References and Notes

1 A Kastrati A Schomig S Elezi H Schuumlhlen J DirschingerM Hadamitzky A Wehinger J Hausleiter H Walter and F JNeumann J Am Coll Cardiol 30 1428 (1997)

2 C Bauters E Huvbert A Prat K Bougrimi E V Belle E PMcFadden P Amouyel J M Lablanche and M Bertrand J AmColl Cardiol 31 1291 (1998)

3 N Mercado E boersma W Wijns B J Gersh C A MorilloV Valk G A van Es D E Grobbee and P W Serruys J AmColl Cardiol 38 645 (2001)

4 J Hausleiter A Kastrati J Mehilli H Schuumlhlen J Pache F DotzerJ Dirschinger and A Schoumlmig J Am Coll Cardiol 40 882 (2002)

5 M N Babapulle L Joseph P Belisle J M Brophy and M JEisenberg Lancet 362 583 (2004)

6 D G Katritsis E Karvouni and J P Ioannidis Am J Cardiol 95640 (2005)

7 W J van der Giessen A M Lincoff R S Schwartz M M vanBeusekom P W Serruys D R Holmes S G Ellis and E J TopolCirculation 94 1690 (1996)

8 Q ji M Miyahara J P Hill S Acharya A Vinu S B YoonJ S Yu K Sakamoto and K Ariga J Am Chem Soc 130 2376(2008)

9 M Saito M Kirihara T Taniguchi and M Miyagi Appl PhysLett 55 607 (1994)

10 D Routkevitch T Bigioni M Moiskovits and J M Xu J PhysChem 100 14037 (1996)

11 A P Li F Muller A Birner K Nielsch and U Gosele J ApplPhys 84 6023 (1998)

12 H El-Sayed S Singh M T Greiner and P Kruse Nano lett 62905 (2006)

13 F Zhang X H Liu C F Pan and J Zhu Nanotechnology 18345302 (2007)

14 H Wieneke O Dirsch T Sawitowski Y L Gu H BrauerU Dahman A Fischer S Wnendt and R Erbel Catheterizationand Cardiovasxular Interventions 60 399 (2003)

15 H J Kang D J Kim S J Park J B Yoo and Y S Ryu ThinSolid Film 515 5184 (2007)

16 H J Kang S J Park J B Yoo and D J Kim Solid State Phe-nomena 124ndash126 (2007)

17 J M Terwogt B Nuijen W W Ten Bokkel Huinink and J HBeijnen Cancer Treat Rev 23 87 (1997)

18 H Shin D K Jeong J Lee M M Sung and J Kim Adv Mater16 1197 (2004)

Received 30 August 2005 Accepted 5 November 2008

348 J Nanosci Nanotechnol 10 345ndash348 2010

Delivered by Ingenta toSung Kyun Kwan University

IP 115145200154Fri 09 Apr 2010 054308

RESEARCH

ARTIC

LE

Kwak et al Drug Release Behavior from Nanoporous Anodic Aluminum Oxide

500

5

10

15

20

25

30

35

40

45

50 A

mou

nt [micro

g]

Time [hour]

pore size 20~30 nmpore size 40~50 nmpore size 50~60 nm standard 60~70 nmpore size 100~150 nm

450400350300250200150100

Fig 3 Cumulative paclitaxel release from the AAO films with variouspore diameters

diameter and depth of the specimen in Figure 1(a) are60ndash70 nm and 2 m respectively Figure 1(e) shows thetop and cross sectional images of the specimen which wasanodized in oxalic and phosphoric acid solution at a volt-age of 195 V The pore diameter and depth of the specimenin Figure 1(e) are 100ndash150 nm and 2 m respectivelyFigures 1(b) (c) and (d) correspond to the specimen

in Figure 1(a) on which TiO2 was deposited in order to

Fig 4 Cross-section and top view ESEM images The secondary anodization was carried out in 03 M oxalic acid at 5 C at 40 V for 8 min (a)15 min (b) and 20 min (c) The thicknesses of the oxide films were determined to be 500 nm 1 m and 4 m respectively

reduce the pore diameter by ALD Pore diameters of about50 40 and 20 nm were obtained after the deposition ofTiO2 for the specimens in Figures 1(b) (c) and (d) respec-tively All of the samples have a uniform pore depth of2 m Figure 2 shows a part of the AAO before andafter drug loading Empty nanopores can be seen beforedrug loading in Figure 2(a) However almost all of thepores were filled with the drug after loading as shown inFigure 2(b) Columns with a bent shape can be seen inthe cross section view (Fig 2(b)) which are consideredto be made up of the drug Figure 3 shows the plot of thecumulative drug release from the AAO films with differ-ent pore diameters Even after 400 hr the drug was stilleluted steadily The amounts of drug released from allof the specimens except for the one with a pore diam-eter of 20ndash30 nm were similar despite the difference inthe pore diameter This result means that the drug releaserate did not depend on the pore diameter The amountof drug released from the specimen with a pore diameterof 20ndash30 nm was larger than that from the other speci-mens However the drug release tendency except for theinitial release period of 120 hr was almost the same Itis believed that a large amount of the loaded drug waslocated on the surface of the specimen with a pore diam-eter of 20ndash30 nm after drug loading and was released inthe early stages

J Nanosci Nanotechnol 10 345ndash348 2010 347

Delivered by Ingenta toSung Kyun Kwan University

IP 115145200154Fri 09 Apr 2010 054308

RESEARCH

ARTIC

LE

Drug Release Behavior from Nanoporous Anodic Aluminum Oxide Kwak et al

00

5

10

15

20

25

Am

ount

[microg]

Time [hour]

500 nm 1 microm 4 microm

21619216814412096724824

Fig 5 Cumulative paclitaxel release from AAO films with various poredepths

In order to investigate the effect of the pore depth on thedrug release three different specimens with different thick-nesses were prepared First using oxalic acid at 5 C as anelectrolyte three identical AAO specimens were producedwith a pore diameter of 40ndash50 nm as shown in Figure 4Then three specimens with pore depths of 500 nm (a)1 m (b) and 4 m (c) were produced by controlling thesecondary anodization time Figure 5 shows the plot of thecumulative drug release from the AAO films with differ-ent pore depths Increasing the pore depth from 05 mto 4 m decreased the amount of drug released In thekinetics of drug release it is believed that the depth of thepores plays an important role as in the case of a diffu-sion controlled reaction When the drug release from thepores occurs through a diffusion controlled process therelease time is proportional to the square of the depthHowever the time-release curve showing the amount ofdrug released as a function of the pore depth in Figure 5did not correspond to that of a diffusion controlled reac-tion It is considered that the drug is released not onlyfrom the bottom but also from the side walls of the poresTherefore the mean diffusion distance may be smallerthan the pore depth

4 CONCLUSION

AAO films were fabricated using a two-step anodizing pro-cess that resulted in a highly uniform pore size and depthdistribution The pore diameter and depth of the AAO filmwere controlled by adjusting the applied voltage and sec-ond anodization time during the anodizing process and

ALD with TiO2 Paclitaxel was used for the drug load-ing and release test The amount of drug released did notdepend on the pore diameter However increasing the poredepth decreased the amount of drug released

Acknowledgment This study was supported by theKorea Science and Engineering Foundation (Grant NoR01-2004-000-10534-0)

References and Notes

1 A Kastrati A Schomig S Elezi H Schuumlhlen J DirschingerM Hadamitzky A Wehinger J Hausleiter H Walter and F JNeumann J Am Coll Cardiol 30 1428 (1997)

2 C Bauters E Huvbert A Prat K Bougrimi E V Belle E PMcFadden P Amouyel J M Lablanche and M Bertrand J AmColl Cardiol 31 1291 (1998)

3 N Mercado E boersma W Wijns B J Gersh C A MorilloV Valk G A van Es D E Grobbee and P W Serruys J AmColl Cardiol 38 645 (2001)

4 J Hausleiter A Kastrati J Mehilli H Schuumlhlen J Pache F DotzerJ Dirschinger and A Schoumlmig J Am Coll Cardiol 40 882 (2002)

5 M N Babapulle L Joseph P Belisle J M Brophy and M JEisenberg Lancet 362 583 (2004)

6 D G Katritsis E Karvouni and J P Ioannidis Am J Cardiol 95640 (2005)

7 W J van der Giessen A M Lincoff R S Schwartz M M vanBeusekom P W Serruys D R Holmes S G Ellis and E J TopolCirculation 94 1690 (1996)

8 Q ji M Miyahara J P Hill S Acharya A Vinu S B YoonJ S Yu K Sakamoto and K Ariga J Am Chem Soc 130 2376(2008)

9 M Saito M Kirihara T Taniguchi and M Miyagi Appl PhysLett 55 607 (1994)

10 D Routkevitch T Bigioni M Moiskovits and J M Xu J PhysChem 100 14037 (1996)

11 A P Li F Muller A Birner K Nielsch and U Gosele J ApplPhys 84 6023 (1998)

12 H El-Sayed S Singh M T Greiner and P Kruse Nano lett 62905 (2006)

13 F Zhang X H Liu C F Pan and J Zhu Nanotechnology 18345302 (2007)

14 H Wieneke O Dirsch T Sawitowski Y L Gu H BrauerU Dahman A Fischer S Wnendt and R Erbel Catheterizationand Cardiovasxular Interventions 60 399 (2003)

15 H J Kang D J Kim S J Park J B Yoo and Y S Ryu ThinSolid Film 515 5184 (2007)

16 H J Kang S J Park J B Yoo and D J Kim Solid State Phe-nomena 124ndash126 (2007)

17 J M Terwogt B Nuijen W W Ten Bokkel Huinink and J HBeijnen Cancer Treat Rev 23 87 (1997)

18 H Shin D K Jeong J Lee M M Sung and J Kim Adv Mater16 1197 (2004)

Received 30 August 2005 Accepted 5 November 2008

348 J Nanosci Nanotechnol 10 345ndash348 2010

Delivered by Ingenta toSung Kyun Kwan University

IP 115145200154Fri 09 Apr 2010 054308

RESEARCH

ARTIC

LE

Drug Release Behavior from Nanoporous Anodic Aluminum Oxide Kwak et al

00

5

10

15

20

25

Am

ount

[microg]

Time [hour]

500 nm 1 microm 4 microm

21619216814412096724824

Fig 5 Cumulative paclitaxel release from AAO films with various poredepths

In order to investigate the effect of the pore depth on thedrug release three different specimens with different thick-nesses were prepared First using oxalic acid at 5 C as anelectrolyte three identical AAO specimens were producedwith a pore diameter of 40ndash50 nm as shown in Figure 4Then three specimens with pore depths of 500 nm (a)1 m (b) and 4 m (c) were produced by controlling thesecondary anodization time Figure 5 shows the plot of thecumulative drug release from the AAO films with differ-ent pore depths Increasing the pore depth from 05 mto 4 m decreased the amount of drug released In thekinetics of drug release it is believed that the depth of thepores plays an important role as in the case of a diffu-sion controlled reaction When the drug release from thepores occurs through a diffusion controlled process therelease time is proportional to the square of the depthHowever the time-release curve showing the amount ofdrug released as a function of the pore depth in Figure 5did not correspond to that of a diffusion controlled reac-tion It is considered that the drug is released not onlyfrom the bottom but also from the side walls of the poresTherefore the mean diffusion distance may be smallerthan the pore depth

4 CONCLUSION

AAO films were fabricated using a two-step anodizing pro-cess that resulted in a highly uniform pore size and depthdistribution The pore diameter and depth of the AAO filmwere controlled by adjusting the applied voltage and sec-ond anodization time during the anodizing process and

ALD with TiO2 Paclitaxel was used for the drug load-ing and release test The amount of drug released did notdepend on the pore diameter However increasing the poredepth decreased the amount of drug released

Acknowledgment This study was supported by theKorea Science and Engineering Foundation (Grant NoR01-2004-000-10534-0)

References and Notes

1 A Kastrati A Schomig S Elezi H Schuumlhlen J DirschingerM Hadamitzky A Wehinger J Hausleiter H Walter and F JNeumann J Am Coll Cardiol 30 1428 (1997)

2 C Bauters E Huvbert A Prat K Bougrimi E V Belle E PMcFadden P Amouyel J M Lablanche and M Bertrand J AmColl Cardiol 31 1291 (1998)

3 N Mercado E boersma W Wijns B J Gersh C A MorilloV Valk G A van Es D E Grobbee and P W Serruys J AmColl Cardiol 38 645 (2001)

4 J Hausleiter A Kastrati J Mehilli H Schuumlhlen J Pache F DotzerJ Dirschinger and A Schoumlmig J Am Coll Cardiol 40 882 (2002)

5 M N Babapulle L Joseph P Belisle J M Brophy and M JEisenberg Lancet 362 583 (2004)

6 D G Katritsis E Karvouni and J P Ioannidis Am J Cardiol 95640 (2005)

7 W J van der Giessen A M Lincoff R S Schwartz M M vanBeusekom P W Serruys D R Holmes S G Ellis and E J TopolCirculation 94 1690 (1996)

8 Q ji M Miyahara J P Hill S Acharya A Vinu S B YoonJ S Yu K Sakamoto and K Ariga J Am Chem Soc 130 2376(2008)

9 M Saito M Kirihara T Taniguchi and M Miyagi Appl PhysLett 55 607 (1994)

10 D Routkevitch T Bigioni M Moiskovits and J M Xu J PhysChem 100 14037 (1996)

11 A P Li F Muller A Birner K Nielsch and U Gosele J ApplPhys 84 6023 (1998)

12 H El-Sayed S Singh M T Greiner and P Kruse Nano lett 62905 (2006)

13 F Zhang X H Liu C F Pan and J Zhu Nanotechnology 18345302 (2007)

14 H Wieneke O Dirsch T Sawitowski Y L Gu H BrauerU Dahman A Fischer S Wnendt and R Erbel Catheterizationand Cardiovasxular Interventions 60 399 (2003)

15 H J Kang D J Kim S J Park J B Yoo and Y S Ryu ThinSolid Film 515 5184 (2007)

16 H J Kang S J Park J B Yoo and D J Kim Solid State Phe-nomena 124ndash126 (2007)

17 J M Terwogt B Nuijen W W Ten Bokkel Huinink and J HBeijnen Cancer Treat Rev 23 87 (1997)

18 H Shin D K Jeong J Lee M M Sung and J Kim Adv Mater16 1197 (2004)

Received 30 August 2005 Accepted 5 November 2008

348 J Nanosci Nanotechnol 10 345ndash348 2010