Materials Science and Engineering C 32 (2012) 1704–1709
Contents lists available at SciVerse ScienceDirect
Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec
Short communication
Hybrid nanostructured drug carrier with tunable and controlled drug release D. Depan, R.D.K. Misra ⁎ Biomaterials and Biomedical Engineering Research Laboratory, Center for Structural and Functional Materials, University of Louisiana at Lafayette, P.O. Box 44130, Lafayette, LA 70504‐4130, USA
a r t i c l e
i n f o
Article history: Received 21 January 2012 Received in revised form 29 March 2012 Accepted 21 April 2012 Available online 28 April 2012 Keywords: Carbon nanotubes Nanohybrid structure Doxorubicin Copolymer Drug release
a b s t r a c t We describe here a transformative approach to synthesize a hybrid nanostructured drug carrier that exhibits the characteristics of controlled drug release. The synthesis of the nanohybrid architecture involved two steps. The first step involved direct crystallization of biocompatible copolymer along the long axis of the carbon nanotubes (CNTs), followed by the second step of attachment of drug molecule to the polymer via hydrogen bonding. The extraordinary inorganic–organic hybrid architecture exhibited high drug loading ability and is physically stable even under extreme conditions of acidic media and ultrasonic irradiation. The temperature and pH sensitive characteristics of the hybrid drug carrier and high drug loading ability merit its consideration as a promising carrier and utilization of the fundamental aspects used for synthesis of other promising drug carriers. The higher drug release response during the application of ultrasonic frequency is ascribed to a cavitation-type process in which the acoustic bubbles nucleate and collapse releasing the drug. Furthermore, the study underscores the potential of uniquely combining CNTs and biopolymers for drug delivery. © 2012 Elsevier B.V. All rights reserved.
1. Introduction The drug delivery process can be defined as administration of a pharmaceutical agent to obtain a therapeutic effect. In conventional drug delivery, the drug is generally administered repetitively at regular intervals to observe the therapeutic effect [1,2]. This procedure, when adopted in situations when the drug is administrated in high dose, may potentially lead to detrimental side effects or undesirable immunological response [3–6]. In recent years, there is a significant attention aimed at minimizing the undesirable effects and facilitating patient compliance. In this regard, particular focus has been given to polymerbased drug delivery carriers that are biodegradable [7–11]. In the design of polymer-based drug carrier, one of the aims is to modify the drug release profile either through chemical or structural design of the drug carrier [12–14]. Here the mechanism of drug release involves either degradation of the polymer via an enzymatic reaction, diffusion of drug through the polymer, or combination of both the processes [13,15–18]. Controlled delivery of drug as schematically illustrated in Fig. 1 is a preferred drug release profile over the conventional drug release because it minimizes or eliminates repetitive administration of drug. This is a challenge that we have addressed in the study described here. An innovative approach to enhance drug loading capability and efficiently tune the drug delivery response is to anchor drug molecules along the long axis of carbon nanotubes (CNTs). Thus, we explore here the extraordinary architecture and large surface area of CNTs to realize
⁎ Corresponding author. E-mail address: [email protected] (R.D.K. Misra). 0928-4931/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.msec.2012.04.045
their potential for drug delivery applications. But one of the difficulties associated with CNTs is the natural tendency of CNTs to aggregate because of strong intertubular van der Waals interactions [19,20]. In the transformative approach described here, we directly crystallize polymer along the long axis of CNTs and subsequently anchor drug molecules to the polymer crystals via chemical bonding. Block copolymers are attractive to prove the feasibility of the aforementioned concept because the two different types of polymer segments are separable from one another because of the immiscibility of the segments [21]. Furthermore, block copolymers enhance the dispersibility and stability of CNTs in a broad range of organic solvents through a dual action, where one block of the polymer interacts with the CNTs, while the second block provides dispersibility and chemical compatibility with the CNTs [22]. Another attractive attribute of alternating block copolymers, excluding random copolymers, is their ability to self-assemble into ordered nanostructures. This potentially acts as a template for CNT alignment at the nanoscale, as demonstrated in this study, enabling synthesis of hybrid drug carrier. Based on the above discussion, an amphiphilic block copolymer, poly(ethylene)-b-poly(polyethylene glycol) (PE-b-PEG) (double crystalline diblock copolymer) was selected. The PE component of the copolymer assisted periodic crystallization along the long axis of CNTs, while the PEG component of the copolymer is hydrophilic and is unique in terms of coordination with water molecules in aqueous solutions [23]. Thus, the amphiphilic diblock copolymer is expected to improve permeability, hydrophilicity, and dispersibility of the CNTbased nanohybrid structure [24]. Moreover, the amphiphilic nature of the copolymer together with the aromatic stacking capability of CNTs is expected to provide high drug loading capability.
D. Depan, R.D.K. Misra / Materials Science and Engineering C 32 (2012) 1704–1709
Drug level
Maximum desired level
1705
Traditional
with minimum loss of time and the resulting product dried at room temperature.
Controlled
2.3. Characterization of polymer-CNT hybrid architecture The morphology, size, and the periodicity of the polymer crystals directly crystallized on the long axis of CNTs was examined using transmission electron microscope (TEM) (Hitachi H-7600), operated at 100 kV. The sample was dispersed in toluene via sonication, and a drop of dispersion was placed on the carbon-coated copper grid and dried at room temperature for examination via TEM.
Minimum desired level
Time Fig. 1. A schematic illustration of traditional and controlled drug release over the course of time.
2.4. Loading of doxorubicin (DOX) on polymer-CNT hybrid architecture Anticancer drug, DOX (30 mg), and polymer-CNT (10 mg) were added to 30 mL PBS (phosphate buffered saline) solution of varying pH (2, 7.4, and 10) and stirred for 16 h at room temperature in dark to decrease the probability of degradation of drug. Different pH were used to determine the optimal pH for maximum loading efficiency. The product (DOX-polymer-CNT) was collected by repeated centrifugation and washing with PBS until the supernatant became colorless. The resulting DOX-polymer-CNT was freeze-dried. The amount of unbound DOX was determined by measuring the absorbance at 490 nm (UV–vis spectrometer; Jasco V-6300) relative to a calibration plot recorded under identical conditions, allowing the drug loading efficiency to be estimated using Eq. (1):
In summary, we describe here the synthesis of a novel drug carrier, where drug molecules are bound via π–π stacking to the polymer crystals that are periodically crystallized along the long axis of CNTs. This nanohybrid architecture provides controlled drug release and is tunable because the periodic spacing between the polymer crystals can be tuned via change in undercooling. 2. Experimental 2.1. Materials Toluene and copolymer, polyethylene-b-poly (ethylene glycol) (PE-b-PEG) (molecular weight 1400 g/mol, 50 wt% PE) were obtained from Sigma-Aldrich. Doxorubicin hydrochloride (DOX) was obtained from Tecoland Corporation, USA. Carbon nanotubes were obtained from Global Nanotech, Mumbai.
%DOX−loading efficiency ¼ 100ðW Feed−DOX −W Free−DOX Þ=W Feed−DOX
ð1Þ
The DOX-loading efficiency estimated was ~ 42% at pH = 2, 61% at pH = 10, and 98% at pH = 7.4.
2.2. Direct crystallization of polymer along the long axis of CNTs
2.5. Characterization of drug carrier and drug release response
A dispersion of single-walled carbon nanotubes (CNTs) (0.4 mg) was prepared in toluene by sonicating for 4 h, followed by probe sonication (Fischer Scientific Ultrasonic FS220H 250 W) for 30 min, reducing the ability of CNTs to agglomerate due to van der Waals force. Next, 1.6 mg of polymer was dissolved in toluene by heating at 110 °C for 60 min. Subsequently, the CNT dispersion was added drop-wise to this solution. The resulting solution (designated: polymer-CNT) was subjected to crystallization at 60 °C for 60 min
Considering that the delivery of drug primarily depends on the nanocarrier, the product obtained at different stages of the synthesis of the hybrid drug carrier was characterized by FTIR (Jasco FT/IR480) and UV–vis spectroscopy. This involved the study of DOX, polymer-CNT, and DOX-polymer-CNT. The drug release profile from the synthesized DOX-polymer-CNT hybrid architecture was studied at the physiological temperature and pH of 37 °C and 7.4, respectively, and also at 40 °C and pH of
a
b
POLYMER/TOLUENE
CNT
110 °C, 1 hr.
CNT/TOLUENEDispersion Sonication
PE-co-PEG CNT/POLYMER/TOLUENE Mixing @ 110°°
CNT
CNT + PE-co-PEG
CNT/POLYMER/TOLUENE
PE-b-PEG
Crystallization @ 60°°C 1 hr.
CNT + PE-co-PEG
CNT-Polymer NANOHYBRID
200 nm Fig. 2. Transmission electron micrograph of polymer (PE-b-PEG) crystallized along the long axis of CNTs and schematic illustration of sequence of steps involving crystallization of polymer as disk-shaped crystals on CNTs.
D. Depan, R.D.K. Misra / Materials Science and Engineering C 32 (2012) 1704–1709
5.3 (the endosomal pH of cancer cells) using a dialysis bag diffusion technique. Briefly, 3 mg of the drug carrier (DOX-polymer-CNT) was sealed in a dialysis membrane tube. The dialyses tube was immersed in 10 mL of Na2HPO4–KH2PO4 buffer solution of pH 5.3 or 7.4 and placed in a test tube, followed by placing it in a water bath maintained at 37 °C or 40 °C. Aliquot containing the drug release medium (~ 2.5 mL) was withdrawn periodically. After each measurement, the aliquot was added back to the release system. The amount of DOX (WFree-DOX) in the buffer solution was quantified using UV–vis absorption spectra as described in Section 2.4. Given that the measurement time was very short, while the drug release predetermined time interval was significantly large, the influence of the returned medium on drug release during the measurement time is expected to be insignificant. All the drug release experiments were repeated at least three times. To evaluate the effect of ultrasonic frequency on drug release, two different power outputs of 100 W and 150 W (Branson 2510) with continuous irradiation were used. The pH of the release media was 7.4, while the temperature was set at 37 °C.
0.50 0.45 238
0.40
Absorbance (a.u.)
1706
DOX-Polymer-CNT
0.35 233
0.30
487 0.25 0.20 0.15 DOX
0.10
480
0.05 0.00 200
300
400
500
600
Wavelength (nm) Fig. 3. UV–vis absorbance spectra of doxorubicin (DOX) and DOX-polymer-CNT hybrid drug carrier. The loading of DOX is evidenced by a shift in the DOX peak from 487 nm to 480 nm.
3. Results and discussion
The structural morphology of polymer crystallized along the long axis of CNTs, as imaged via transmission electron microscopy (TEM), is presented in Fig. 2 together with steps involved in the crystallization process. The experimental approach described in Section 2.2 led to crystallization of a number of disk-shaped polymer crystals in a periodic manner along the long axis of CNTs (Fig. 2). The periodic spacing between the polymer crystals was ~50–70 nm, and crystal diameter and thickness were ~40–60 nm and ~15–20 nm, respectively. It may be noted that the periodic growth of polymer crystals is not a consequence of shear flow because the solution was stationary, but is related to CNT-induced nucleation. The underlying reason for periodic crystallization of disk-shaped polymer crystals is either governed by (a) geometric confinement of CNTs or (b) epitaxial growth, and is being studied from the view point of polymer physics [25]. Currently, we believe that the periodic crystallization is related to cumulative effect of geometrical confinement effect and the structure of polymer. 3.2. Anchoring of DOX to polymer-CNT hybrid architecture The –OH group of DOX is involved in hydrogen bonding with the hydrogen of PEG part of the copolymer. Similarly –OH group of PEG interacts with –NH2 of DOX. The anchoring of DOX to the polymer crystallized along the long axis of CNTs was confirmed by UV–vis spectroscopy (Fig. 3). The peak of DOX appears at 233 and 480 nm. When DOX interacts with the crystallized polymer via hydrogen bonding, there was a red-shift, and the relevant peaks of DOX at 233 and 480 nm shifted to 238 and 487 nm, respectively. Confirmation of interaction of DOX with crystallized polymer on CNTs was obtained by Fourier transform infrared (FTIR) spectroscopy, which is an appropriate technique to study the interaction between the different constituents of the nanostructured hybrid drug carrier. The FTIR data is summarized in Fig. 4 and Table 1. In the case of polymer-CNT hybrid architecture, the broad peak around 3550 cm− 1 is due to stretching vibration band of OH, and the peaks at 1340 cm− 1 and 1282 cm− 1 are associated with CNT stretching vibrations. The main aspect to be noted is that peak at 1732 cm− 1 corresponding to carbonyl stretching vibration of DOX shifted to a lower position of 1725 cm− 1 in the polymer-CNT drug carrier. We now discuss the drug loading capability. Considering the above discussion on the nature of chemical bonding between DOX
and crystallized polymer along the long axis of CNTs, the drug loading efficiency is expected to be related to the conjugation of –NH2 and – OH groups in DOX to the polymer crystallized on CNTs. The drug loading efficiency of nanostructured hybrid carrier was significantly high at 98% at pH 7.4, while at pH 10 was 61%, and 42% at pH 2. 3.3. Drug release: the effect of pH and temperature The factors that determine the drug release depend on pH and temperature of the release media, for a given structure of the nanocarrier. As discussed in the experimental section, the drug release was studied at the physiological pH of 7.4 and the slightly acidic endosomal pH of 5.3 of tumor cells. Fig. 5 shows that there is initially a linear release of drug with time followed by controlled release over
a) Polymer-CNT 718 3550-3400
Transmittance (Arb. Units)
3.1. Structural morphology of PE-b-PEG crystallized on the long axis of CNTs
1468 1282 843 950 1340 1110
2915
b) DOX
764
1732
3450 3334
816 1115
2925 1620 1583
1725
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1071
1414
c) DOX-Polymer-CNT
720
1352
1575
1463
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940
2853 1112
2914
4000
3500
3000
2500
2000
1500
1000
500
Wavenumber (cm-1) Fig. 4. Fourier transform infrared (FTIR) spectra of (a) polymer-CNT hybrid structure, (b) DOX, and (c) DOX-polymer-CNT hybrid nanostructured carrier.
D. Depan, R.D.K. Misra / Materials Science and Engineering C 32 (2012) 1704–1709 Table 1 Assignment of FTIR spectra of CNT-polymer, DOX, and DOX-CNT-polymer nanohybrid drug carrier, as presented in Fig. 4. Samples
IR absorption bands (cm− 1)
Descriptiona
(i) CNT-polymer
3550–3400 2915 1468 1340 1282 1110 950 843 718 3450 3334 2925 1732
ν (O―H) ν (− CH2) δ (− CH3) νas (C―O―C) ν (C―C) ν (C―O) δ (–CH–) C―H deformation –CH2– swing in-plane vibration ν (N―H) ν (O―H) ν (C―H) ν (C―O) Quinone and ketone carbonyls δ (N―H) δ (N―H) ν (C―C) ν (C―O) ν (C―O) ω (N―H) ω (N―H) δ (N―H) ν (O―H) ν (–CH2) ν (O―H) of DOX νs(C―O―CH3) of DOX δ (N―H) of DOX δ (–CH3) νas (C―O―C) ν (C―C) ν (C―O) δ (–CH–) –CH2– swing in-plane vibration
(ii) DOX
1620 1583 1414 1115 1071 871 816 764 3430 2914 2853 1725 1575 1463 1352 1255 1112 940 720
(iii) DOX-polymerCNT
a ν = stretching vibration, νs = symmetric stretching vibration; νas = asymmetric stretching vibration; δ = bending vibration; w = wagging.
extended period of time. Controlled release of drug is a significant result. As kinetically expected, the release is greater at 40 °C as compared to 37 °C, and the initial rapid release is most likely to be rapid burst release of drug. Similarly, temperature has a direct influence on the swelling and release behavior. Temperature affects the segmental mobility of the polymer chains. The presence of high temperature enables faster relaxation of the polymer network and hence swelling, facilitating water sorption [26]. On the other hand, the difference in drug release at the investigated pH of 5.3 and 7.4 is related to the differences in the swelling capability of the polymer at the
1707
respective pH. The swelling capability of polymer is a large scale deformation process and is discussed elsewhere [27]. The swelling capability of the polymer was greater in the acidic pH of 5.3 as compared to the physiological pH of 7.4. At low pH, the hydrogen bonding interaction between the DOX and polymer weakens, and accordingly greater amount of drug is released. At physiological pH and temperature, the swelling and relaxation of polymeric macromolecular chains is less, which results in lower concentration of drug release. 3.4. The effect of application of ultrasonic irradiation on drug release We have explored here the effect of ultrasonic frequency on the drug release response. Ultrasonic irradiation is expected to play an ever increasing role in the delivery of therapeutic agent and is a promising external trigger for drug delivery because the release rate of the drug can be tuned via application of different frequency of ultrasonic irradiation to the drug release medium. It is clear from Fig. 6 that the amount of drug release was increased significantly and was a function of the applied power of the ultrasonic irradiation. However, the controlled release behavior was retained after the initial rapid release. It may be noted that to investigate the effect of ultrasonic frequency on drug release, the samples were immersed in the release media (pH 7.4), and kept in a bath, maintained at a constant temperature (37 °C). It was observed that DOX was continuously released and amount of DOX released was increased significantly when the power of ultrasonic irradiation was increased from 100 W to 150 W. The amount of drug released after 30 min of ultrasonic irradiation was nearly doubled as compared to the amount released under silent conditions, suggesting that the ultrasonic frequency has an apparent effect in enhancing the drug release kinetics. The higher release of drug during ultrasonic irradiation can be explained as due to ultrasonic irradiation-induced loosening of rigid packing of the hydrocarbon chains [28], which results in increase in the permeability of water and drug through the polymer. Furthermore, the drug release profile was similar to that observed at pH 7.4/37 °C (Fig. 6). The underlying reason is that the ultrasonic radiation overrides any effect the pH and temperature may have through cavitation-induced by the ultrasonic irradiation that opens up the polymeric shell and the encapsulated drug diffuses out in the release media. Our drug delivery system consists of CNT and polymer, in which the polymeric chains are aligned along the long axis of CNTs. When such a three-dimensional nanocarrier is subjected to ultrasonic frequency, a disorganization of the polymer chains and subsequent formation of transport channels in the three-dimensional network 60
45
55 40oC, pH 5.3
40
DOX Released (%)
DOX Released (%)
35 30
37oC, pH 5.3
25 40oC, pH 7.4
20 15
37oC, pH 7.4
10
Ultrasonic Frequency (150 W)
50 45 40 35 30
Ultrasonic Frequency (100 W)
25 20 15
Silent Condition
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0 0
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90
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40
Time (min)
Time (min) Fig. 5. The release of DOX from the hybrid nanostructured drug carrier at two different temperatures of 37 °C and 40 °C and pH of 5.3 and 7.4.
Fig. 6. The release of doxorubicin from the hybrid nanostructured drug carrier in the presence and absence of an external trigger (ultrasonic irradiation). The pH was 7.4, and the temperature of ultrasonic water bath was set at 37 °C.
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D. Depan, R.D.K. Misra / Materials Science and Engineering C 32 (2012) 1704–1709
occurs. These effects can be explained in terms of cavitation phenomenon that is generated during ultrasonic irradiation [29], such that acoustic bubbles form and burst in an adiabatic fashion, producing conditions of temperature and pressure. The drug release pattern also indicates good stability of the nanocarrier, suggesting that amphiphilicity and ultrasonic susceptibility of hybrid nanocarrier assembly make it possible for the ultrasonic irradiation to penetrate deep into the three-dimensional assembly comprised of CNTs and polymer. Our findings are clinically important in a situation where a continuous controlled release of a therapeutically effective dose is required. These characteristics can be developed as a potentially useful strategy for the in-vivo smart control of drug. Currently, a number of drug delivery carriers are based on the detachment and diffusion of drug, which has limitation in clinical situations such as diabetes, where the patient generally requires a high dose of insulin after meals. Thus, a drug delivery system with sufficiently high drug loading ability such as the one described here is expected to enable real-time control of drug dosage based on changes in chemical and physiological status. The drug delivery system explored in the present study represents an example of smart control, in which the loading efficiency was significantly higher than conventional nanocarriers. The release system was sensitive to pH and temperature of the release media. Furthermore,
the encapsulated drug molecules can be subjected to trigger release via ultrasonic irradiation, as schematically illustrated in Fig. 7. Generally, the drug delivery systems based on polymers experience mechanical damage after the release experiments and surface rupture due to the cavitation process induced by the ultrasonic irradiation. The physical stability of the nanocarrier was investigated after 60 min of release experiment under physiological conditions (pH 7.4 and 37 °C temperature) and 60 min of ultrasonic irradiation. The sample was dried and examined under transmission electron microscope. As shown in Fig. 8, there were no noticeable differences in the physical structure of the hybrid nanocarrier, suggesting the physical stability of the hybrid nanostructured carrier. Thus, in summary the proposed hybrid nanostructured system involving periodic crystallization of polymer along the long axis of CNTs followed by subsequent attachment of drug molecules to the crystallized polymer is a promising approach to obtain controlled release of drug with high drug loading ability. A broad impact of the proposed approach is that other polymers such as nylon 6,6 can be crystallized along the long axis of CNTs and appropriately used as a drug delivery carrier. The most important aspect of the hybrid nanostructured approach is that it allows us to tune the amount of drug that can be incorporated into the nanocarrier, by controlling the periodic spacing between the disk-shaped polymer crystals. This can be accomplished
a H
OH m
O
n
Polymer
CNTs
Crystallized Polymer on CNTs
b
Crystallized Polymer on CNTs
Doxorubicin (DOX)
DOX-Polymer-CNT
c
Ultrasound
DOX-Polymer-CNT
Released DOX
Hydrophobic Chain H
OH m
O
n
Hydrophilic Chain DOX
H-bonding interactions between DOX and Polymer Fig. 7. Schematic illustration of encapsulation of DOX within the CNT-polymer nanohybrid drug carrier, and US triggered release of DOX from CNT-polymer nanohybrid.
D. Depan, R.D.K. Misra / Materials Science and Engineering C 32 (2012) 1704–1709
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drug delivery. We envision that the proposed approach with the advantages of high drug loading ability and the property of stimuliresponsive controlled release is expected to play a significant role in the development of new generation, site specific, and smart drug release. Lastly, the high drug release response during application of ultrasonic irradiation is ascribed to a cavitation-type process in which acoustic bubbles nucleate and burst releasing the drug.
References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Fig. 8. Transmission electron micrograph of DOX nanocarrier (CNT-polymer) after completion of release experiment illustrating stability after 60 min of ultrasonic irradiation of 150 W, pH 7.4 release media.
[11] [12]
via a change in undercooling (ΔT) (ΔT = difference in equilibrium melting point of the polymer and crystallization temperature). A higher undercooling will lead to greater number of small nuclei to be stable along the long axis of CNTs such that the periodic spacing between the disk-shaped polymer crystals (observed in Fig. 2) will be reduced. A large number of disks will allow for higher concentration of drug to be attached to the polymer surface via hydrogen bonding, such that more drug molecules will be released at a given set of experimental conditions. 4. Conclusions We have successfully synthesized and demonstrated the efficacy of an inorganic–organic hybrid nanostructured drug carrier that is characterized by anchoring of drug molecules to the disk-shaped polymer crystals along the long axis of carbon nanotubes. This hybrid nanostructured carrier has high drug loading capability with characteristics of controlled release. The drug release was sensitive towards pH and temperature. This dual-sensitivity and high drug loading makes the proposed approach merit consideration for controlled
[13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25]
[26] [27] [28] [29]
J. Kost, R. Langer, Adv. Drug Deliv. Rev. 46 (2001) 125–148. K. Soppimath, D. Tan, Y. Yang, Adv. Mater. 17 (2005) 318–323. L. Gerweck, K. Seetharaman, Cancer Res. 56 (1996) 1194–1198. D.B. Leeper, K. Engin, A.J. Thistlethwaite, H.D. Hitchon, J.D. Dover, D.J. Li, L. Tupchong, Int. J. Radiat. Oncol. Biol. Phys. 28 (1994) 935–943. C.R. Ganorkar, F. Liu, M. Baudys, S. Kim, J. Control. Release 59 (1999) 287–298. S. Kang, K. Na, Y. Bae, Colloids Surf. A 231 (2003) 103–112. C. Lo, K. Lin, G. Hsiue, J. Control. Release 104 (2005) 477–488. L. Lacerda, A. Bianco, M. Prato, K. Kostarelos, Adv. Drug Deliv. Rev. 58 (2006) 1460–1470. M. Bottini, N. Rosato, N. Bottini, Biomacromolecules 12 (2011) 3381–3393. Z. Liu, C. Davis, W. Cau, L. He, X. Chen, H. Dai, Proc. Natl. Acad. Sci. U. S. A. 105 (2008) 1410–1415. G. Minnoti, P. Menna, E. Salvatorelli, G. Cairo, L. Gianni, Pharmacol. Rev. 56 (2) (2004) 185–229. G.A. Husseini, G.D. Myrup, W.G. Pitt, D.A. Christensen, N.J. Rapoport, J. Control. Release 69 (2000) 43–52. D. Depan, J.S. Shah, R.D.K. Misra, Mater Sci Eng C 31 (2011) 1305–1312. X.B. Xiong, A. Falamarzian, S.M. Garg, A. Lavasanifar, J. Control. Release 155 (2011) 248–261. T. Etrych, L. Kovar, J. Strohalm, P. Chytil, B. Rihova, K. Ulbrich, J. Control. Release 154 (2011) 241–248. M. Moniruzzaman, K.I. Winey, Macromolecules 39 (2006) 5194–5205. Zhuang Liu, Xiaoming Sun, Nozomi Nakayama-Ratchford, Hongjie Dai, ACS Nano 1 (1) (2007) 50. H. Kim, H. Matsuda, H. Zhou, I. Honma, Adv. Mater. 18 (2006) 3083–3088. D. Tasis, N. Tagmatarchis, A. Bianco, M. Prato, Chem. Rev. 106 (2006) 1105–1136. N. Grossiord, J. Loos, O. Regev, C.E. Koning, Chem. Mater. 18 (2006) 1089–1099. I.W. Hamley, The Physics of Block Copolymers, Oxford University Press, New York, 1998. Bing Li, Lingyu Li, Bingbing Wang, Christopher Y. Li, Nat. Nanotechnol. 4 (2009) 358. D. Cho, Y.J. Kim, C. Erkey, J.T. Koberstein, Macromolecules 38 (2005) 1829–1836. J.H. Lee, H.B. Lew, J.D. Andrade, Prog. Polym. Sci. 201 (1996) 1043. R.D.K. Misra, Z. Jia, H.Z. Huang, Q. Yuan, J.S. Shah, Tunable nanometer-scale architecture of organic–inorganic hybrid nanostructured materials for structural and functional applications, (2012). http://dx.doi.org/10.1002/macp.201100503. A.K. Bajpai, R. Saini, Polym. Int. 54 (5) (2005) 796. R.D.K. Misra, Q. Yuan, Mater. Sci. Eng. C 32 (2012) 902–908. E.B. Flint, K.S. Suslick, Science 253 (1991) 1397–1399. N.Y. Rapoport, D.A. Christensen, H.D. Fain, L. Barrows, Z. Gao, Ultrasonics 42 (2004) 943–950.
Contents lists available at SciVerse ScienceDirect
Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec
Short communication
Hybrid nanostructured drug carrier with tunable and controlled drug release D. Depan, R.D.K. Misra ⁎ Biomaterials and Biomedical Engineering Research Laboratory, Center for Structural and Functional Materials, University of Louisiana at Lafayette, P.O. Box 44130, Lafayette, LA 70504‐4130, USA
a r t i c l e
i n f o
Article history: Received 21 January 2012 Received in revised form 29 March 2012 Accepted 21 April 2012 Available online 28 April 2012 Keywords: Carbon nanotubes Nanohybrid structure Doxorubicin Copolymer Drug release
a b s t r a c t We describe here a transformative approach to synthesize a hybrid nanostructured drug carrier that exhibits the characteristics of controlled drug release. The synthesis of the nanohybrid architecture involved two steps. The first step involved direct crystallization of biocompatible copolymer along the long axis of the carbon nanotubes (CNTs), followed by the second step of attachment of drug molecule to the polymer via hydrogen bonding. The extraordinary inorganic–organic hybrid architecture exhibited high drug loading ability and is physically stable even under extreme conditions of acidic media and ultrasonic irradiation. The temperature and pH sensitive characteristics of the hybrid drug carrier and high drug loading ability merit its consideration as a promising carrier and utilization of the fundamental aspects used for synthesis of other promising drug carriers. The higher drug release response during the application of ultrasonic frequency is ascribed to a cavitation-type process in which the acoustic bubbles nucleate and collapse releasing the drug. Furthermore, the study underscores the potential of uniquely combining CNTs and biopolymers for drug delivery. © 2012 Elsevier B.V. All rights reserved.
1. Introduction The drug delivery process can be defined as administration of a pharmaceutical agent to obtain a therapeutic effect. In conventional drug delivery, the drug is generally administered repetitively at regular intervals to observe the therapeutic effect [1,2]. This procedure, when adopted in situations when the drug is administrated in high dose, may potentially lead to detrimental side effects or undesirable immunological response [3–6]. In recent years, there is a significant attention aimed at minimizing the undesirable effects and facilitating patient compliance. In this regard, particular focus has been given to polymerbased drug delivery carriers that are biodegradable [7–11]. In the design of polymer-based drug carrier, one of the aims is to modify the drug release profile either through chemical or structural design of the drug carrier [12–14]. Here the mechanism of drug release involves either degradation of the polymer via an enzymatic reaction, diffusion of drug through the polymer, or combination of both the processes [13,15–18]. Controlled delivery of drug as schematically illustrated in Fig. 1 is a preferred drug release profile over the conventional drug release because it minimizes or eliminates repetitive administration of drug. This is a challenge that we have addressed in the study described here. An innovative approach to enhance drug loading capability and efficiently tune the drug delivery response is to anchor drug molecules along the long axis of carbon nanotubes (CNTs). Thus, we explore here the extraordinary architecture and large surface area of CNTs to realize
⁎ Corresponding author. E-mail address: [email protected] (R.D.K. Misra). 0928-4931/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.msec.2012.04.045
their potential for drug delivery applications. But one of the difficulties associated with CNTs is the natural tendency of CNTs to aggregate because of strong intertubular van der Waals interactions [19,20]. In the transformative approach described here, we directly crystallize polymer along the long axis of CNTs and subsequently anchor drug molecules to the polymer crystals via chemical bonding. Block copolymers are attractive to prove the feasibility of the aforementioned concept because the two different types of polymer segments are separable from one another because of the immiscibility of the segments [21]. Furthermore, block copolymers enhance the dispersibility and stability of CNTs in a broad range of organic solvents through a dual action, where one block of the polymer interacts with the CNTs, while the second block provides dispersibility and chemical compatibility with the CNTs [22]. Another attractive attribute of alternating block copolymers, excluding random copolymers, is their ability to self-assemble into ordered nanostructures. This potentially acts as a template for CNT alignment at the nanoscale, as demonstrated in this study, enabling synthesis of hybrid drug carrier. Based on the above discussion, an amphiphilic block copolymer, poly(ethylene)-b-poly(polyethylene glycol) (PE-b-PEG) (double crystalline diblock copolymer) was selected. The PE component of the copolymer assisted periodic crystallization along the long axis of CNTs, while the PEG component of the copolymer is hydrophilic and is unique in terms of coordination with water molecules in aqueous solutions [23]. Thus, the amphiphilic diblock copolymer is expected to improve permeability, hydrophilicity, and dispersibility of the CNTbased nanohybrid structure [24]. Moreover, the amphiphilic nature of the copolymer together with the aromatic stacking capability of CNTs is expected to provide high drug loading capability.
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Drug level
Maximum desired level
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Traditional
with minimum loss of time and the resulting product dried at room temperature.
Controlled
2.3. Characterization of polymer-CNT hybrid architecture The morphology, size, and the periodicity of the polymer crystals directly crystallized on the long axis of CNTs was examined using transmission electron microscope (TEM) (Hitachi H-7600), operated at 100 kV. The sample was dispersed in toluene via sonication, and a drop of dispersion was placed on the carbon-coated copper grid and dried at room temperature for examination via TEM.
Minimum desired level
Time Fig. 1. A schematic illustration of traditional and controlled drug release over the course of time.
2.4. Loading of doxorubicin (DOX) on polymer-CNT hybrid architecture Anticancer drug, DOX (30 mg), and polymer-CNT (10 mg) were added to 30 mL PBS (phosphate buffered saline) solution of varying pH (2, 7.4, and 10) and stirred for 16 h at room temperature in dark to decrease the probability of degradation of drug. Different pH were used to determine the optimal pH for maximum loading efficiency. The product (DOX-polymer-CNT) was collected by repeated centrifugation and washing with PBS until the supernatant became colorless. The resulting DOX-polymer-CNT was freeze-dried. The amount of unbound DOX was determined by measuring the absorbance at 490 nm (UV–vis spectrometer; Jasco V-6300) relative to a calibration plot recorded under identical conditions, allowing the drug loading efficiency to be estimated using Eq. (1):
In summary, we describe here the synthesis of a novel drug carrier, where drug molecules are bound via π–π stacking to the polymer crystals that are periodically crystallized along the long axis of CNTs. This nanohybrid architecture provides controlled drug release and is tunable because the periodic spacing between the polymer crystals can be tuned via change in undercooling. 2. Experimental 2.1. Materials Toluene and copolymer, polyethylene-b-poly (ethylene glycol) (PE-b-PEG) (molecular weight 1400 g/mol, 50 wt% PE) were obtained from Sigma-Aldrich. Doxorubicin hydrochloride (DOX) was obtained from Tecoland Corporation, USA. Carbon nanotubes were obtained from Global Nanotech, Mumbai.
%DOX−loading efficiency ¼ 100ðW Feed−DOX −W Free−DOX Þ=W Feed−DOX
ð1Þ
The DOX-loading efficiency estimated was ~ 42% at pH = 2, 61% at pH = 10, and 98% at pH = 7.4.
2.2. Direct crystallization of polymer along the long axis of CNTs
2.5. Characterization of drug carrier and drug release response
A dispersion of single-walled carbon nanotubes (CNTs) (0.4 mg) was prepared in toluene by sonicating for 4 h, followed by probe sonication (Fischer Scientific Ultrasonic FS220H 250 W) for 30 min, reducing the ability of CNTs to agglomerate due to van der Waals force. Next, 1.6 mg of polymer was dissolved in toluene by heating at 110 °C for 60 min. Subsequently, the CNT dispersion was added drop-wise to this solution. The resulting solution (designated: polymer-CNT) was subjected to crystallization at 60 °C for 60 min
Considering that the delivery of drug primarily depends on the nanocarrier, the product obtained at different stages of the synthesis of the hybrid drug carrier was characterized by FTIR (Jasco FT/IR480) and UV–vis spectroscopy. This involved the study of DOX, polymer-CNT, and DOX-polymer-CNT. The drug release profile from the synthesized DOX-polymer-CNT hybrid architecture was studied at the physiological temperature and pH of 37 °C and 7.4, respectively, and also at 40 °C and pH of
a
b
POLYMER/TOLUENE
CNT
110 °C, 1 hr.
CNT/TOLUENEDispersion Sonication
PE-co-PEG CNT/POLYMER/TOLUENE Mixing @ 110°°
CNT
CNT + PE-co-PEG
CNT/POLYMER/TOLUENE
PE-b-PEG
Crystallization @ 60°°C 1 hr.
CNT + PE-co-PEG
CNT-Polymer NANOHYBRID
200 nm Fig. 2. Transmission electron micrograph of polymer (PE-b-PEG) crystallized along the long axis of CNTs and schematic illustration of sequence of steps involving crystallization of polymer as disk-shaped crystals on CNTs.
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5.3 (the endosomal pH of cancer cells) using a dialysis bag diffusion technique. Briefly, 3 mg of the drug carrier (DOX-polymer-CNT) was sealed in a dialysis membrane tube. The dialyses tube was immersed in 10 mL of Na2HPO4–KH2PO4 buffer solution of pH 5.3 or 7.4 and placed in a test tube, followed by placing it in a water bath maintained at 37 °C or 40 °C. Aliquot containing the drug release medium (~ 2.5 mL) was withdrawn periodically. After each measurement, the aliquot was added back to the release system. The amount of DOX (WFree-DOX) in the buffer solution was quantified using UV–vis absorption spectra as described in Section 2.4. Given that the measurement time was very short, while the drug release predetermined time interval was significantly large, the influence of the returned medium on drug release during the measurement time is expected to be insignificant. All the drug release experiments were repeated at least three times. To evaluate the effect of ultrasonic frequency on drug release, two different power outputs of 100 W and 150 W (Branson 2510) with continuous irradiation were used. The pH of the release media was 7.4, while the temperature was set at 37 °C.
0.50 0.45 238
0.40
Absorbance (a.u.)
1706
DOX-Polymer-CNT
0.35 233
0.30
487 0.25 0.20 0.15 DOX
0.10
480
0.05 0.00 200
300
400
500
600
Wavelength (nm) Fig. 3. UV–vis absorbance spectra of doxorubicin (DOX) and DOX-polymer-CNT hybrid drug carrier. The loading of DOX is evidenced by a shift in the DOX peak from 487 nm to 480 nm.
3. Results and discussion
The structural morphology of polymer crystallized along the long axis of CNTs, as imaged via transmission electron microscopy (TEM), is presented in Fig. 2 together with steps involved in the crystallization process. The experimental approach described in Section 2.2 led to crystallization of a number of disk-shaped polymer crystals in a periodic manner along the long axis of CNTs (Fig. 2). The periodic spacing between the polymer crystals was ~50–70 nm, and crystal diameter and thickness were ~40–60 nm and ~15–20 nm, respectively. It may be noted that the periodic growth of polymer crystals is not a consequence of shear flow because the solution was stationary, but is related to CNT-induced nucleation. The underlying reason for periodic crystallization of disk-shaped polymer crystals is either governed by (a) geometric confinement of CNTs or (b) epitaxial growth, and is being studied from the view point of polymer physics [25]. Currently, we believe that the periodic crystallization is related to cumulative effect of geometrical confinement effect and the structure of polymer. 3.2. Anchoring of DOX to polymer-CNT hybrid architecture The –OH group of DOX is involved in hydrogen bonding with the hydrogen of PEG part of the copolymer. Similarly –OH group of PEG interacts with –NH2 of DOX. The anchoring of DOX to the polymer crystallized along the long axis of CNTs was confirmed by UV–vis spectroscopy (Fig. 3). The peak of DOX appears at 233 and 480 nm. When DOX interacts with the crystallized polymer via hydrogen bonding, there was a red-shift, and the relevant peaks of DOX at 233 and 480 nm shifted to 238 and 487 nm, respectively. Confirmation of interaction of DOX with crystallized polymer on CNTs was obtained by Fourier transform infrared (FTIR) spectroscopy, which is an appropriate technique to study the interaction between the different constituents of the nanostructured hybrid drug carrier. The FTIR data is summarized in Fig. 4 and Table 1. In the case of polymer-CNT hybrid architecture, the broad peak around 3550 cm− 1 is due to stretching vibration band of OH, and the peaks at 1340 cm− 1 and 1282 cm− 1 are associated with CNT stretching vibrations. The main aspect to be noted is that peak at 1732 cm− 1 corresponding to carbonyl stretching vibration of DOX shifted to a lower position of 1725 cm− 1 in the polymer-CNT drug carrier. We now discuss the drug loading capability. Considering the above discussion on the nature of chemical bonding between DOX
and crystallized polymer along the long axis of CNTs, the drug loading efficiency is expected to be related to the conjugation of –NH2 and – OH groups in DOX to the polymer crystallized on CNTs. The drug loading efficiency of nanostructured hybrid carrier was significantly high at 98% at pH 7.4, while at pH 10 was 61%, and 42% at pH 2. 3.3. Drug release: the effect of pH and temperature The factors that determine the drug release depend on pH and temperature of the release media, for a given structure of the nanocarrier. As discussed in the experimental section, the drug release was studied at the physiological pH of 7.4 and the slightly acidic endosomal pH of 5.3 of tumor cells. Fig. 5 shows that there is initially a linear release of drug with time followed by controlled release over
a) Polymer-CNT 718 3550-3400
Transmittance (Arb. Units)
3.1. Structural morphology of PE-b-PEG crystallized on the long axis of CNTs
1468 1282 843 950 1340 1110
2915
b) DOX
764
1732
3450 3334
816 1115
2925 1620 1583
1725
3430
1071
1414
c) DOX-Polymer-CNT
720
1352
1575
1463
1255
940
2853 1112
2914
4000
3500
3000
2500
2000
1500
1000
500
Wavenumber (cm-1) Fig. 4. Fourier transform infrared (FTIR) spectra of (a) polymer-CNT hybrid structure, (b) DOX, and (c) DOX-polymer-CNT hybrid nanostructured carrier.
D. Depan, R.D.K. Misra / Materials Science and Engineering C 32 (2012) 1704–1709 Table 1 Assignment of FTIR spectra of CNT-polymer, DOX, and DOX-CNT-polymer nanohybrid drug carrier, as presented in Fig. 4. Samples
IR absorption bands (cm− 1)
Descriptiona
(i) CNT-polymer
3550–3400 2915 1468 1340 1282 1110 950 843 718 3450 3334 2925 1732
ν (O―H) ν (− CH2) δ (− CH3) νas (C―O―C) ν (C―C) ν (C―O) δ (–CH–) C―H deformation –CH2– swing in-plane vibration ν (N―H) ν (O―H) ν (C―H) ν (C―O) Quinone and ketone carbonyls δ (N―H) δ (N―H) ν (C―C) ν (C―O) ν (C―O) ω (N―H) ω (N―H) δ (N―H) ν (O―H) ν (–CH2) ν (O―H) of DOX νs(C―O―CH3) of DOX δ (N―H) of DOX δ (–CH3) νas (C―O―C) ν (C―C) ν (C―O) δ (–CH–) –CH2– swing in-plane vibration
(ii) DOX
1620 1583 1414 1115 1071 871 816 764 3430 2914 2853 1725 1575 1463 1352 1255 1112 940 720
(iii) DOX-polymerCNT
a ν = stretching vibration, νs = symmetric stretching vibration; νas = asymmetric stretching vibration; δ = bending vibration; w = wagging.
extended period of time. Controlled release of drug is a significant result. As kinetically expected, the release is greater at 40 °C as compared to 37 °C, and the initial rapid release is most likely to be rapid burst release of drug. Similarly, temperature has a direct influence on the swelling and release behavior. Temperature affects the segmental mobility of the polymer chains. The presence of high temperature enables faster relaxation of the polymer network and hence swelling, facilitating water sorption [26]. On the other hand, the difference in drug release at the investigated pH of 5.3 and 7.4 is related to the differences in the swelling capability of the polymer at the
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respective pH. The swelling capability of polymer is a large scale deformation process and is discussed elsewhere [27]. The swelling capability of the polymer was greater in the acidic pH of 5.3 as compared to the physiological pH of 7.4. At low pH, the hydrogen bonding interaction between the DOX and polymer weakens, and accordingly greater amount of drug is released. At physiological pH and temperature, the swelling and relaxation of polymeric macromolecular chains is less, which results in lower concentration of drug release. 3.4. The effect of application of ultrasonic irradiation on drug release We have explored here the effect of ultrasonic frequency on the drug release response. Ultrasonic irradiation is expected to play an ever increasing role in the delivery of therapeutic agent and is a promising external trigger for drug delivery because the release rate of the drug can be tuned via application of different frequency of ultrasonic irradiation to the drug release medium. It is clear from Fig. 6 that the amount of drug release was increased significantly and was a function of the applied power of the ultrasonic irradiation. However, the controlled release behavior was retained after the initial rapid release. It may be noted that to investigate the effect of ultrasonic frequency on drug release, the samples were immersed in the release media (pH 7.4), and kept in a bath, maintained at a constant temperature (37 °C). It was observed that DOX was continuously released and amount of DOX released was increased significantly when the power of ultrasonic irradiation was increased from 100 W to 150 W. The amount of drug released after 30 min of ultrasonic irradiation was nearly doubled as compared to the amount released under silent conditions, suggesting that the ultrasonic frequency has an apparent effect in enhancing the drug release kinetics. The higher release of drug during ultrasonic irradiation can be explained as due to ultrasonic irradiation-induced loosening of rigid packing of the hydrocarbon chains [28], which results in increase in the permeability of water and drug through the polymer. Furthermore, the drug release profile was similar to that observed at pH 7.4/37 °C (Fig. 6). The underlying reason is that the ultrasonic radiation overrides any effect the pH and temperature may have through cavitation-induced by the ultrasonic irradiation that opens up the polymeric shell and the encapsulated drug diffuses out in the release media. Our drug delivery system consists of CNT and polymer, in which the polymeric chains are aligned along the long axis of CNTs. When such a three-dimensional nanocarrier is subjected to ultrasonic frequency, a disorganization of the polymer chains and subsequent formation of transport channels in the three-dimensional network 60
45
55 40oC, pH 5.3
40
DOX Released (%)
DOX Released (%)
35 30
37oC, pH 5.3
25 40oC, pH 7.4
20 15
37oC, pH 7.4
10
Ultrasonic Frequency (150 W)
50 45 40 35 30
Ultrasonic Frequency (100 W)
25 20 15
Silent Condition
10 5
5
0 0
0 0
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20
30
40
50
60
70
80
90
5
10
15
20
25
30
35
40
Time (min)
Time (min) Fig. 5. The release of DOX from the hybrid nanostructured drug carrier at two different temperatures of 37 °C and 40 °C and pH of 5.3 and 7.4.
Fig. 6. The release of doxorubicin from the hybrid nanostructured drug carrier in the presence and absence of an external trigger (ultrasonic irradiation). The pH was 7.4, and the temperature of ultrasonic water bath was set at 37 °C.
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occurs. These effects can be explained in terms of cavitation phenomenon that is generated during ultrasonic irradiation [29], such that acoustic bubbles form and burst in an adiabatic fashion, producing conditions of temperature and pressure. The drug release pattern also indicates good stability of the nanocarrier, suggesting that amphiphilicity and ultrasonic susceptibility of hybrid nanocarrier assembly make it possible for the ultrasonic irradiation to penetrate deep into the three-dimensional assembly comprised of CNTs and polymer. Our findings are clinically important in a situation where a continuous controlled release of a therapeutically effective dose is required. These characteristics can be developed as a potentially useful strategy for the in-vivo smart control of drug. Currently, a number of drug delivery carriers are based on the detachment and diffusion of drug, which has limitation in clinical situations such as diabetes, where the patient generally requires a high dose of insulin after meals. Thus, a drug delivery system with sufficiently high drug loading ability such as the one described here is expected to enable real-time control of drug dosage based on changes in chemical and physiological status. The drug delivery system explored in the present study represents an example of smart control, in which the loading efficiency was significantly higher than conventional nanocarriers. The release system was sensitive to pH and temperature of the release media. Furthermore,
the encapsulated drug molecules can be subjected to trigger release via ultrasonic irradiation, as schematically illustrated in Fig. 7. Generally, the drug delivery systems based on polymers experience mechanical damage after the release experiments and surface rupture due to the cavitation process induced by the ultrasonic irradiation. The physical stability of the nanocarrier was investigated after 60 min of release experiment under physiological conditions (pH 7.4 and 37 °C temperature) and 60 min of ultrasonic irradiation. The sample was dried and examined under transmission electron microscope. As shown in Fig. 8, there were no noticeable differences in the physical structure of the hybrid nanocarrier, suggesting the physical stability of the hybrid nanostructured carrier. Thus, in summary the proposed hybrid nanostructured system involving periodic crystallization of polymer along the long axis of CNTs followed by subsequent attachment of drug molecules to the crystallized polymer is a promising approach to obtain controlled release of drug with high drug loading ability. A broad impact of the proposed approach is that other polymers such as nylon 6,6 can be crystallized along the long axis of CNTs and appropriately used as a drug delivery carrier. The most important aspect of the hybrid nanostructured approach is that it allows us to tune the amount of drug that can be incorporated into the nanocarrier, by controlling the periodic spacing between the disk-shaped polymer crystals. This can be accomplished
a H
OH m
O
n
Polymer
CNTs
Crystallized Polymer on CNTs
b
Crystallized Polymer on CNTs
Doxorubicin (DOX)
DOX-Polymer-CNT
c
Ultrasound
DOX-Polymer-CNT
Released DOX
Hydrophobic Chain H
OH m
O
n
Hydrophilic Chain DOX
H-bonding interactions between DOX and Polymer Fig. 7. Schematic illustration of encapsulation of DOX within the CNT-polymer nanohybrid drug carrier, and US triggered release of DOX from CNT-polymer nanohybrid.
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drug delivery. We envision that the proposed approach with the advantages of high drug loading ability and the property of stimuliresponsive controlled release is expected to play a significant role in the development of new generation, site specific, and smart drug release. Lastly, the high drug release response during application of ultrasonic irradiation is ascribed to a cavitation-type process in which acoustic bubbles nucleate and burst releasing the drug.
References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Fig. 8. Transmission electron micrograph of DOX nanocarrier (CNT-polymer) after completion of release experiment illustrating stability after 60 min of ultrasonic irradiation of 150 W, pH 7.4 release media.
[11] [12]
via a change in undercooling (ΔT) (ΔT = difference in equilibrium melting point of the polymer and crystallization temperature). A higher undercooling will lead to greater number of small nuclei to be stable along the long axis of CNTs such that the periodic spacing between the disk-shaped polymer crystals (observed in Fig. 2) will be reduced. A large number of disks will allow for higher concentration of drug to be attached to the polymer surface via hydrogen bonding, such that more drug molecules will be released at a given set of experimental conditions. 4. Conclusions We have successfully synthesized and demonstrated the efficacy of an inorganic–organic hybrid nanostructured drug carrier that is characterized by anchoring of drug molecules to the disk-shaped polymer crystals along the long axis of carbon nanotubes. This hybrid nanostructured carrier has high drug loading capability with characteristics of controlled release. The drug release was sensitive towards pH and temperature. This dual-sensitivity and high drug loading makes the proposed approach merit consideration for controlled
[13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25]
[26] [27] [28] [29]
J. Kost, R. Langer, Adv. Drug Deliv. Rev. 46 (2001) 125–148. K. Soppimath, D. Tan, Y. Yang, Adv. Mater. 17 (2005) 318–323. L. Gerweck, K. Seetharaman, Cancer Res. 56 (1996) 1194–1198. D.B. Leeper, K. Engin, A.J. Thistlethwaite, H.D. Hitchon, J.D. Dover, D.J. Li, L. Tupchong, Int. J. Radiat. Oncol. Biol. Phys. 28 (1994) 935–943. C.R. Ganorkar, F. Liu, M. Baudys, S. Kim, J. Control. Release 59 (1999) 287–298. S. Kang, K. Na, Y. Bae, Colloids Surf. A 231 (2003) 103–112. C. Lo, K. Lin, G. Hsiue, J. Control. Release 104 (2005) 477–488. L. Lacerda, A. Bianco, M. Prato, K. Kostarelos, Adv. Drug Deliv. Rev. 58 (2006) 1460–1470. M. Bottini, N. Rosato, N. Bottini, Biomacromolecules 12 (2011) 3381–3393. Z. Liu, C. Davis, W. Cau, L. He, X. Chen, H. Dai, Proc. Natl. Acad. Sci. U. S. A. 105 (2008) 1410–1415. G. Minnoti, P. Menna, E. Salvatorelli, G. Cairo, L. Gianni, Pharmacol. Rev. 56 (2) (2004) 185–229. G.A. Husseini, G.D. Myrup, W.G. Pitt, D.A. Christensen, N.J. Rapoport, J. Control. Release 69 (2000) 43–52. D. Depan, J.S. Shah, R.D.K. Misra, Mater Sci Eng C 31 (2011) 1305–1312. X.B. Xiong, A. Falamarzian, S.M. Garg, A. Lavasanifar, J. Control. Release 155 (2011) 248–261. T. Etrych, L. Kovar, J. Strohalm, P. Chytil, B. Rihova, K. Ulbrich, J. Control. Release 154 (2011) 241–248. M. Moniruzzaman, K.I. Winey, Macromolecules 39 (2006) 5194–5205. Zhuang Liu, Xiaoming Sun, Nozomi Nakayama-Ratchford, Hongjie Dai, ACS Nano 1 (1) (2007) 50. H. Kim, H. Matsuda, H. Zhou, I. Honma, Adv. Mater. 18 (2006) 3083–3088. D. Tasis, N. Tagmatarchis, A. Bianco, M. Prato, Chem. Rev. 106 (2006) 1105–1136. N. Grossiord, J. Loos, O. Regev, C.E. Koning, Chem. Mater. 18 (2006) 1089–1099. I.W. Hamley, The Physics of Block Copolymers, Oxford University Press, New York, 1998. Bing Li, Lingyu Li, Bingbing Wang, Christopher Y. Li, Nat. Nanotechnol. 4 (2009) 358. D. Cho, Y.J. Kim, C. Erkey, J.T. Koberstein, Macromolecules 38 (2005) 1829–1836. J.H. Lee, H.B. Lew, J.D. Andrade, Prog. Polym. Sci. 201 (1996) 1043. R.D.K. Misra, Z. Jia, H.Z. Huang, Q. Yuan, J.S. Shah, Tunable nanometer-scale architecture of organic–inorganic hybrid nanostructured materials for structural and functional applications, (2012). http://dx.doi.org/10.1002/macp.201100503. A.K. Bajpai, R. Saini, Polym. Int. 54 (5) (2005) 796. R.D.K. Misra, Q. Yuan, Mater. Sci. Eng. C 32 (2012) 902–908. E.B. Flint, K.S. Suslick, Science 253 (1991) 1397–1399. N.Y. Rapoport, D.A. Christensen, H.D. Fain, L. Barrows, Z. Gao, Ultrasonics 42 (2004) 943–950.
