<?xml version="1.0" encoding="UTF-8"?><!DOCTYPE article  PUBLIC "-//NLM//DTD Journal Publishing DTD v3.0 20080202//EN" "http://dtd.nlm.nih.gov/publishing/3.0/journalpublishing3.dtd"><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" dtd-version="3.0" xml:lang="en" article-type="research article"><front><journal-meta><journal-id journal-id-type="publisher-id">JBNB</journal-id><journal-title-group><journal-title>Journal of Biomaterials and Nanobiotechnology</journal-title></journal-title-group><issn pub-type="epub">2158-7027</issn><publisher><publisher-name>Scientific Research Publishing</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.4236/jbnb.2012.32022</article-id><article-id pub-id-type="publisher-id">JBNB-18934</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biomedical&amp;Life Sciences</subject><subject> Chemistry&amp;Materials Science</subject></subj-group></article-categories><title-group><article-title>
 
 
  Multifunctional Nanostructured Materials Applied in Controlled Radiopharmaceuticals Release
 
</article-title></title-group><contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>aquel</surname><given-names>Cristina de Sousa Azevedo</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Daniel</surname><given-names>Crístian Ferreira Soares</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Ricardo</surname><given-names>Geraldo de Sousa</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Edésia</surname><given-names>Martins Barros de Sousa</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff2"><addr-line>Departamento de Engenharia Química, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.</addr-line></aff><aff id="aff1"><addr-line>Centro de Desenvolvimento da Tecnologia Nuclear (CDTN)/CNEN, Servi?o de Nanotecnologia, Belo Horizonte, Brazil</addr-line></aff><author-notes><corresp id="cor1">* E-mail:<email>sousaem@cdtn.br(EMBDS)</email>;</corresp></author-notes><pub-date pub-type="epub"><day>28</day><month>04</month><year>2012</year></pub-date><volume>03</volume><issue>02</issue><fpage>163</fpage><lpage>168</lpage><history><date date-type="received"><day>January</day>	<month>6th,</month>	<year>2012</year></date><date date-type="rev-recd"><day>February</day>	<month>24th,</month>	<year>2012</year>	</date><date date-type="accepted"><day>March</day>	<month>13th,</month>	<year>2012</year></date></history><permissions><copyright-statement>&#169; Copyright  2014 by authors and Scientific Research Publishing Inc. </copyright-statement><copyright-year>2014</copyright-year><license><license-p>This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/</license-p></license></permissions><abstract><p>
 
 
  The metaiodobenzylguanidine (MIBG) radiopharmaceutical, an analogue of norepinephrine, has been used to diagnose certain diseases in the cardiovascular system when radiolabeled with 
  <sup>123</sup>I. This radiopharmaceutical can also be used to treat tumors, such as neuroblastomas and pheochromocytomas, when radiolabeled with 
  <sup>131</sup>I. Its clinical use is often accompanied by a slow intravenous administration, where a significant dose of radiation can directly affect workers in nuclear medicine services. To overcome this problem, the incorporation and controlled release of radiopharmaceuticals from the matrix of mesoporous systems based on silica, such as SBA-15 and hybrid [SBA-15/P(
  N-iPAAm)], can lead to a significant reduction in radiation doses received by workers. In the present study, silica matrices SBA-15 and hybrid [SBA-15/P(
  N-iPAAm)] containing the radiopharmaceutical MIBG were prepared and physicochemically characterized through FTIR, SEM, and small angle X-ray diffraction techniques. The release profiles of MIBG from SBA-15 and [SBA-15/P(
  N-iPAAm)] were studied in a simulated body fluid (SBF) to evaluate their potential application as vehicles for controlled releases. Furthermore, in vitro studies were performed to assess the cytotoxicity of matrices as compared to human lung fibroblast cells (MRC-5). The results revealed that the amount of MIBG incorporated within the studied matrices was indeed quite different, showing that only the hybrid [SBA-15/P(
  N-iPAAm)] system allowed for a more adequate release profile of MIGB. Taking all results into consideration, it can be concluded that the hybrid matrix [SBA-15/P(
  N-iPAAm)] can be considered a potential alternative material for the controlled release delivery of radio-pharmaceuticals.
 
</p></abstract><kwd-group><kwd>SAB-15; Hybrid [SBA-15/P(N-iPAAm)]</kwd><kwd> MIGB Radiopharmaceutical; Drug Release</kwd></kwd-group></article-meta></front><body><sec id="s1"><title>1. Introduction</title><p>The Metaiodobenzylguanidine (MIBG) radiopharmaceutical is an analogue of norepinephrine, which competes for capture, accumulation, and release processes in adrenergic nerve endings. MIBG is not metabolized by Catechol-O-Methyl-Transferase (COMT) and Monoamine Oxidase (MAO), which, once radiolabeled with <sup>123</sup>I, allows for its use in the noninvasive evaluation of the adrenergic activity of the cardiovascular system, providing valuable prognostic information [1-4]. Furthermore, MIBG can be used in tumor treatments, such as neuroblastomas and pheochromocytomas, when radiolabeled with <sup>131</sup>I [5-7]. The clinical use of MIBG is often accompanied by a slow intravenous administration, where a significant dose of radiation can directly affect workers in nuclear medicine services [8-10].</p><p>One means through which to solve this problem is the use of implants composed of materials that can promote the controlled release of the radiopharmaceutical, thus avoiding the presence of workers during the infusion process. In this context, ordered mesoporous materials have been the subject of a growing number of studies in different applications, including the controlled release of drugs [11,12]. The mesoporous silica with hexagonal structure, SBA-15, presents an ordered hexagonal arrangement of unidirectional mesoporous channels containing a diameter of approximately 6 to 10 nm; a high surface area of above 800 m<sup>2</sup>/g, depending on the synthesis conditions; and good thermal and hydrothermal stability [13,14]. Due to these structural characteristics, SBA-15 materials present a high potential for the incorporation and release of a wide variety of molecules (organic and inorganic) that can provide therapeutic activities [15,16].</p><p>Temperature-responsive hydrogels, such as poly(Nisopropylacrylamide) P(N-iPAAm), are also a well-studied class of drug delivery systems, as they can respond pronouncedly to temperature changes [17-20]. In water, P(N-iPAAm) exhibits a phase transition at a lower critical solution temperature (LCST) of approximately 33˚C. Below the LCST, the hydrogel incorporates water and swells, whereas the release of water in response to an increase in temperature causes shrinkage [21,22].</p><p>Therefore, the combination of the mesoporous material SBA-15 with the polymeric gel poly(N-isopropylacrylamide) can lead to the formation of a hybrid material with a potential for application as new drug delivery systems, given that self-regulated delivery allows for drug release when needed [<xref ref-type="bibr" rid="scirp.18934-ref23">23</xref>].</p><p>Some studies on hybrid systems based on P(N-iPAAm) and ordered mesoporous materials have been reported in the literature and have shown interesting results [24-26]. Studies have found that the resultant hybrid systems, as compared to pure polymers, exhibit an increased mechanical and chemical performance and even unique properties due to their regular mesoscopic structure and space restriction effect [17,27]. In this sense, the incorporation of the polymer phase into mesoporous silica can led to a significant change in the structural properties of the system without destroying the ordered hexagonal structure of SBA-15, which makes this system promising for a variety of intelligent applications, especially in the controlled release of the radiopharmaceutical.</p><p>Considering that the special properties of these hybrid systems are useful in various structural and biomedical applications due to their specific characteristics, the present work aimed to evaluate a special synthesis route to obtain [SBA-15/P(N-iPAAm)]. This study investigated the cytotoxicity of both samples by MTT assay, as well as the influence of the presence of a polymeric species within SBA-15 on the behavior of silica matrices as a controlled drug release device, and compared the release kinetics of the model drug (MIBG) from pure SBA-15.</p></sec><sec id="s2"><title>2. Experimental</title><sec id="s2_1"><title>2.1. Synthesis</title><p>SBA-15 silica was prepared according to Zhao [<xref ref-type="bibr" rid="scirp.18934-ref14">14</xref>] using commercial triblock copolymer Pluronic P123—PEO20- PPO70-PEO20 [poly(ethylene glycol)-block-poly (propylene glycol)-block-poly(ethylene glycol)] (Sigma-Aldrich) as a templating agent. The P123 copolymer was dissolved in a mixture of distilled water and HCl under stirring, followed by the addition of tetraethyl orthosilicate (TEOS). The mixture was maintained at 35˚C for 24 h, and then for an additional 24 h at 100˚C under static conditions in a Teflon-lined autoclave. The obtained material was filtered and dried at 40˚C and the surfactant was removed by calcination (550˚C for 5 h).</p><p>The hybrid was prepared using the following procedure [<xref ref-type="bibr" rid="scirp.18934-ref28">28</xref>]: 0.5 g of calcined SBA-15 was added to a 3.5 mL solution of 0.245 g of monomer (N-isopropylacrylamide—N-iPAAm) and 0.005 g of crosslinking agent (N,N,N’, N’-methylene-bisacrylamide—MBA). The mixture was transferred to an INNOVA 4200 (150 rpm) shaker, and the mixture was continuously purged with nitrogen. The solution was then allowed to polymerize for 24 h in a water bath at 10˚C. The obtained hybrid material was dried at 60˚C for 24 h and subsequently washed to remove the excess of monomers, crosslinking agent, initiator, and accelerator. In the washing stage, the material was disaggregated, suspended in water, and continually stirred. The hybrid was then collected by centrifugation at 3600 rpm for 3 min and dried at 60˚C for 24 h [<xref ref-type="bibr" rid="scirp.18934-ref29">29</xref>].</p></sec><sec id="s2_2"><title>2.2. Characterization</title><p>The FTIR measurements were conducted with an ABB Bomen model MB102 spectrophotometer within the range of 4000 - 400 cm<sup>–</sup><sup>1</sup>. The FTIR spectra were recorded at room temperature using KBr pellets and a resolution of 4 cm<sup>–1</sup> and 64 scans/min. SEM characterization was performed in a scanning electron microscope (Quanta 200 FEG-FEI) operating at 30 kV. The small-angle XRD patterns were obtained using an Ultima IV &#174; (Rigaku Inc.) 3 kW generator rotating equipment anode X-ray diffraction equipped with a copper anode (λ = 1.54 Ǻ). The generator was operated at 40 kV and 30 mA. The incident X-ray was set at a wavelength of 1.488 &#197;, while the angle scattering 2θ ranged from 0˚ to 5˚.</p></sec><sec id="s2_3"><title>2.3. MIBG Loading and in Vitro Release Study</title><p>SBA-15 and [SBA-15/P(N-iPAAm)] were loaded with Metaiodobenzylguanidine (MIBG) as follows: 0.2 g of the powder sample was added to 25 mL of an MIBG solution (800 &#181;g&#183;mL<sup>–1</sup>) and shaken for 48 h at 25˚C (200 rpm). A 1:10 weight ratio of the MIBG/solid sample was used. Powder MIBG-loaded samples were recovered by filtration, washed with distilled water, and left to dry for 24 h at 60˚C. The in vitro release profile was obtained by soaking the samples (50 mg) in 30 mL of a simulated body fluid (SBF) [<xref ref-type="bibr" rid="scirp.18934-ref30">30</xref>] for 24hs at room temperature. The UV spectrometry procedure (Shimadzu UV-VIS V-V 2550) was used to monitor the amount of MIBG that had been loaded and released as a function of time. The solutions were continuously stirred, and the concentration of MIBG in SBF was determined by the intensity of the absorption band at 230 nm.</p></sec><sec id="s2_4"><title>2.4. Cytotoxicity Study</title><p>The cytotoxicity of SBA-15 and [SBA-15/P(N-iPAAm)] were evaluated by means of MTT ((3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay in human lung fibroblast cells (MRC-5), obtained from the radiobiology laboratory from the Center for the Development of Nuclear Technology (CDTN/CNEN).</p><p>The cells (1500 cells/well) were subjected to treatment for 48 hours, under increasing concentrations of SBA-15 and [SBA-15/P(N-iPAAm)] (0.1 to 200 μg&#183;mL<sup>–</sup><sup>1</sup>). Eight replicates were investigated for statistical evaluation. The determination of the absorbance at 570 nm of the formed product is a measure of metabolic cell viability, and both quantities are directly proportional.</p></sec><sec id="s2_5"><title>2.5. Statistics</title><p>All experiments were performed in triplicate and expressed as the mean &#177; standard deviation, unless otherwise stated. The specific activity data were compared by means of the Student’s t-test, using the prism 4.0 software, considering a 95% confidence interval.</p></sec></sec><sec id="s3"><title>3. Results and Discussion</title><sec id="s3_1"><title>3.1. Synthesis</title><p><xref ref-type="fig" rid="fig1">Figure 1</xref> shows the FTIR spectra of all studied samples. The spectra of pure SBA-15 and the hybrid sample exhibited different absorption bands. The SBA-15 spectrum was dominated by nO-H modes, presenting a broad and intense band at 3440 cm<sup>–</sup><sup>1</sup> assigned to hydroxyl groups. A broad and very intense band in the range 1000 - 1200 cm<sup>-1</sup>, corresponding to nSi-O-Si modes of the SBA-15 siliceous matrix, was also present. The band at 960 cm<sup>–</sup><sup>1</sup> could be assigned to δ (HOH) physisorbed water and the Si-O stretching vibration of surface Si-OH groups. In hybrid systems, the bands corresponding to the nC-H modes of P(N-iPAAm) are commonly observed between 2972 and 2875 cm<sup>–</sup><sup>1</sup>; the bands attributed to the isopropyl group were located at 1386 and 1368 cm<sup>–</sup><sup>1</sup>; the band corresponding to the bending vibration of CH<sub>3</sub> was located at 1456 cm<sup>–</sup><sup>1</sup>; while the bands arising from C=O stretching and N-H bending vibrations were observed at 1645 and 1550 cm<sup>–</sup><sup>1</sup>, respectively.</p><p>The monomer characteristic bands (nC=C 1620 cm<sup>–</sup><sup>1</sup>; dCH<sub>2</sub> = 1409 cm<sup>–</sup><sup>1</sup>; dH<sub>2</sub>C=C- 1305 and 1325 cm<sup>–</sup><sup>1</sup>; dvinyl group at 990 and 916 cm<sup>–</sup><sup>1</sup>) were not present in the hybrid sample spectra, as can be seen in the scale-expanded FTIR spectrum in the 1800 - 900 cm<sup>–</sup><sup>1</sup> region (<xref ref-type="fig" rid="fig2">Figure 2</xref>). These results prove the presence of P(N-iPAAm) in SBA- 15 pores with no other significant synthesis components (monomer, initiator, or accelerator) and demonstrate the successful conversion of the monomers into polymer [<xref ref-type="bibr" rid="scirp.18934-ref29">29</xref>].</p><p><xref ref-type="fig" rid="fig3">Figure 3</xref> shows SEM images of the SBA-15 and [SBA-15/P(N-iPAAm)] samples. SBA-15 consists of many rope-like domains with average sizes of 1.7 μm aggregated into wheat-like macrostructures, <xref ref-type="fig" rid="fig3">Figure 3</xref>(a). A</p></sec></sec></body><back><ref-list><title>References</title><ref id="scirp.18934-ref1"><label>1</label><mixed-citation publication-type="other" xlink:type="simple">J. W. Ha, J.-D. Lee, Y. Jang, N. Chung, J. Kwan, S.-J.  Rim, Y.-J. Lee and S.-S. Kim, “123I-MIBG Myocardial Scintigraphy as a Noninvasive Screen for the Diagnosis of Coronary Artery Spasm,” Journal of Nuclear Cardiol- ogy, Vol. 5, No. 6, 1998, pp. 591-597.  
doi:10.1016/S1071-3581(98)90113-1</mixed-citation></ref><ref id="scirp.18934-ref2"><label>2</label><mixed-citation publication-type="other" xlink:type="simple">H. Ogita, T. Shimonagata, M. Fukunami, et al., “Prognostic Significance of Cardiac 123I Metaiodobenzylguanidine Imaging for Mortality and Morbidity in Patients with Chronic Heart Failure: A Prospective Study,” Heart, Vol. 86, No. 6, 2001, 656-660.  
doi:10.1136/heart.86.6.656</mixed-citation></ref><ref id="scirp.18934-ref3"><label>3</label><mixed-citation publication-type="other" xlink:type="simple">D. Agostini, I. Carrió and H. J. Verbene, “How to Use Myocardial 123I-MIBG Scintigraphy in Chronic Heart Failure,” European Journal of Nuclear Medicine and Molecular Imaging, Vol. 36, No. 4, 2009, 555-559.  
doi:10.1007/s00259-008-0976-x</mixed-citation></ref><ref id="scirp.18934-ref4"><label>4</label><mixed-citation publication-type="other" xlink:type="simple">A. F. Jacobson, J. Lombard, G. Banerjee, et al., “123I-MIBG Scintigraphy to Predict Risk for Adverse Cardiac Outcomes in Heart Failure Patients: Design of Two Prospective Multicenter International Trials,” Journal of Nuclear Cardiology, Vol. 16, No. 1, 2009, 113-121.  
doi:10.1007/s12350-008-9008-2</mixed-citation></ref><ref id="scirp.18934-ref5"><label>5</label><mixed-citation publication-type="other" xlink:type="simple">K. S. S. Bhati, M. M. Ismail, A. Sahdev, A. G. Rockall, K. Hogarth, A. Canizales, N. Avril, J. P. Monson, A. B. Grossman and R. H. Reznek, “123I-Metaiodobenzylguanidine (MIBG) Scintigraphy for the Detection of Adrenal and Extra-Adrenal Phaeochromocytomas: CT and MRI Correlation,” Clinical Endocrinology, Vol. 69, No. 2, 2008, 181-188. doi:10.1111/j.1365-2265.2008.03256.x</mixed-citation></ref><ref id="scirp.18934-ref6"><label>6</label><mixed-citation publication-type="other" xlink:type="simple">B. Rose, K. K. Matthay, D. Price, J. Huberty, B. Klencke, J. A. Norton, et al., “High-Dose 131I Metaiodobenzyl-guanidine Therapy for 12 Patients with Malignant Pheochromocy-toma,” Cancer, Vol. 98, No. 2, 2003, 239-248.  
doi:10.1002/cncr.11518</mixed-citation></ref><ref id="scirp.18934-ref7"><label>7</label><mixed-citation publication-type="other" xlink:type="simple">J. Rob, Mairs, Boyd, “Op-timizing MIBG Therapy of Neuroendocrine Tumors: Preclinical Evidence of Dose Maximization and Synergy,” Nuclear Medicine and Biology, Vol. 35, No. 1, 2008, 9-20.  
doi:10.1016/j.nucmedbio.2008.04.008</mixed-citation></ref><ref id="scirp.18934-ref8"><label>8</label><mixed-citation publication-type="other" xlink:type="simple">J. B. Bomanji, W. Wong, M. N. A. Gaze, W. Cassoni, J. S. Waddington and P. J. Ell, “Treatment of Neuroendocrine Tumours in Adults with 131I-MIBG Therapy,” Clinical Oncology, Vol. 15, No. , 2003, 193-198.  
doi:10.1016/S0936-6555(02)00273-X</mixed-citation></ref><ref id="scirp.18934-ref9"><label>9</label><mixed-citation publication-type="other" xlink:type="simple">F. Giammarile, A. Chiti, M. Lassmann, B. Brans and G. Flux, “EANM Procedure Guidelines for 131I-Meta-Iodo- benzylguanidine (131I-mIBG) Therapy,” European Jour- nal of Nuclear Medicine and Molecular Imaging, Vol. 35, No. 5, 2008, 1039-1047.  
doi:10.1007/s00259-008-0715-3</mixed-citation></ref><ref id="scirp.18934-ref10"><label>10</label><mixed-citation publication-type="journal" xlink:type="simple"><name name-style="western"><surname>L. Troncone and V. Rufini</surname><given-names> “131I-MIBG Therapy of Neural Crest Tumours </given-names></name>,<etal>et al</etal>. (<year>Review</year>)<article-title>,” Anticancer Research, Vol. 17, No</article-title><source> 3</source><volume> 1997</volume>,<fpage> 1823</fpage>-<lpage>1831</lpage>.<pub-id pub-id-type="doi"></pub-id></mixed-citation></ref><ref id="scirp.18934-ref11"><label>11</label><mixed-citation publication-type="other" xlink:type="simple">A. Taguchi and F. Schüth, “Ordered Mesoporous Materials in Catalysis,” Microporous and Mesoporous Materials, Vol. 77, No. 1, 2005, pp. 1-45.  
doi:10.1016/j.micromeso.2004.06.030</mixed-citation></ref><ref id="scirp.18934-ref12"><label>12</label><mixed-citation publication-type="other" xlink:type="simple">S. Wang, “Ordered Mesoporous Materials for Drug Delivery,” Microporous and Mesoporous Materials, Vol. 117, No. 1-2, 2009, pp. 1-9.  
doi:10.1016/j.micromeso.2008.07.002</mixed-citation></ref><ref id="scirp.18934-ref13"><label>13</label><mixed-citation publication-type="other" xlink:type="simple">U. Ciesla and F. Schüth, “Ordered Mesoporous Materials,” Micro-porous and Mesoporous Materials, Vol. 27, No. 2-3, 1999, pp. 131-149.  
doi:10.1016/S1387-1811(98)00249-2</mixed-citation></ref><ref id="scirp.18934-ref14"><label>14</label><mixed-citation publication-type="other" xlink:type="simple">D. Zhao, Q. Huo, J. Feng, B. F. Chmelka and G. D. Stucky, “Nonionic Triblock and Star Diblock Copolymer and Oligomeric Surfactant Syntheses of Highly Ordered, Hydrothermally Stable, Mesoporous Sílica Structures,” Journal of the American Chemical Society, Vol. 120, No. 24, 1998, pp. 6024-6036. doi:10.1021/ja974025i</mixed-citation></ref><ref id="scirp.18934-ref15"><label>15</label><mixed-citation publication-type="other" xlink:type="simple">J. S. Beck and J. C. Vartuli, “Recent Advances in the Synthesis, Characterization and Applications of Mesoporous Molecular Sieves,” Current Opinion in Solid State &amp; Materials Science, Vol. 1, No. 1, 1996, pp. 76-87.  
doi:10.1016/S1359-0286(96)80014-3</mixed-citation></ref><ref id="scirp.18934-ref16"><label>16</label><mixed-citation publication-type="other" xlink:type="simple">M. Hartmann, “Ordered Mesoporous Materials for Bioad- sorption and Biocatalysis,” Chemistry of Materials, Vol. 17, No. 18, 2005, pp. 4577-4593.  
doi:10.1021/cm0485658</mixed-citation></ref><ref id="scirp.18934-ref17"><label>17</label><mixed-citation publication-type="other" xlink:type="simple">D. C. Coughlan, F. P. Quilty and O. I. Corrigan, “Effect of Drug Physicho-chemical Properties on Swelling/Des-welling Kinetics and Pulsatile Drug Release from Thermoresponsive Poly(N-isopropylacrylamide) Hydrogels,” Journal of Controlled Release, Vol. 98, No. 1, 2006, pp. 97-114. doi:10.1016/j.jconrel.2004.04.014</mixed-citation></ref><ref id="scirp.18934-ref18"><label>18</label><mixed-citation publication-type="other" xlink:type="simple">A. S. Hoffman, “Applications of Thermally Reversible Polymers and Hydrogels in Therapeutics and Diagnostics,” Journal of Controlled Release, Vol. 6, No. 1, 1987, pp. 297-305. doi:10.1016/0168-3659(87)90083-6</mixed-citation></ref><ref id="scirp.18934-ref19"><label>19</label><mixed-citation publication-type="other" xlink:type="simple">N. A. Peppas, “Hydrogels in Pharmaceutical Formulations,” European Journal of Pharmaceutics and Biophar- maceutics, Vol. 50, No. 1, 2000, pp. 27-46.  
doi:10.1016/S0939-6411(00)00090-4</mixed-citation></ref><ref id="scirp.18934-ref20"><label>20</label><mixed-citation publication-type="other" xlink:type="simple">N. A. Peppas and R. Langer, “Advances in Biomaterials, Drug Delivery, and Bionanotechnology,” Bioengineering, Food, and Natural Products, Vol. 49 No. 12, 2003, pp. 2990-3006. doi:10.1002/aic.690491202</mixed-citation></ref><ref id="scirp.18934-ref21"><label>21</label><mixed-citation publication-type="other" xlink:type="simple">R. F. S. Freitas and E. L. Cussler, “Temperature Sensitive Gels as Extraction Solvents,” Chemical Engineering Science, Vol. 42, No. 1, 1987, pp. 97-103.  
doi:10.1016/0009-2509(87)80213-0</mixed-citation></ref><ref id="scirp.18934-ref22"><label>22</label><mixed-citation publication-type="other" xlink:type="simple">R. F. S. Freitas and E. L. Cussler, “Temperature Sensitive Gels as Size Selective Absorbants,” Separation Science and Technology, Vol. 22, No. 2-3, 1987, pp. 911-919.  
doi:10.1080/01496398708068989</mixed-citation></ref><ref id="scirp.18934-ref23"><label>23</label><mixed-citation publication-type="other" xlink:type="simple">V. Castelvetro and C. De Vitaa, “Nanostructured Hybrid Materials from Aqueous Polymer Dispersions,” Advances in Colloid and Interface Science, Vol. 108-109, 2004, pp. 167-185. doi:10.1016/j.cis.2003.10.017</mixed-citation></ref><ref id="scirp.18934-ref24"><label>24</label><mixed-citation publication-type="other" xlink:type="simple">Y. Chun and B.-S. Tian, “Preparation and Characterization of Thermo-Sensitive Mesoporous PNIPAAm/SBA- 15 Composite,” Acta Chimica Sinica, Vol. 66, No. 5, 2008, pp. 505-510. </mixed-citation></ref><ref id="scirp.18934-ref25"><label>25</label><mixed-citation publication-type="other" xlink:type="simple">S. Zhu, Z. Zhou, D. Zhang, C. Jin and Z. Li, “Design and Synthesis of Delivery System Based on SBA-15 with Magnetic Particles Formed in Situ and Thermo-Sensitive P-Napalm as Controlled Switch,” Microporous and Meso- porous Materials, Vol. 106, No. 1-3, 2007, pp. 56-61.  
doi:10.1016/j.micromeso.2007.02.027</mixed-citation></ref><ref id="scirp.18934-ref26"><label>26</label><mixed-citation publication-type="other" xlink:type="simple">Z. Zhou, S. Zhu and D. Zhang, “Grafting of Thermo-Responsive Polymer inside Mesoporous Silica with Large Pore Size Using ATRP and Investigation of Its Use in Drug Release,” Journal of Materials Chemistry, Vol. 17, No. 23, 2007, pp. 2428-2433. doi:10.1039/b618834f</mixed-citation></ref><ref id="scirp.18934-ref27"><label>27</label><mixed-citation publication-type="other" xlink:type="simple">A. Sousa and E. M. B. Sousa, “Influence of Synthesis Temperature on the Structural Characteristics of Mesoporous Silica,” Journal of Non-Crystalline Solids, Vol. 352, No. 32-35, 2006, pp. 3451-3456.  
doi:10.1016/j.jnoncrysol.2006.03.080</mixed-citation></ref><ref id="scirp.18934-ref28"><label>28</label><mixed-citation publication-type="other" xlink:type="simple">R. G. Sousa, “Structural Characterization of the Gel Thermosensitive Poly(N-isopropylacrylamide) and Its Copolymers with Acrylamide,” Ph.D. Thesis, Federal University of Minas Gerais, Belo Horizonte, 1997.</mixed-citation></ref><ref id="scirp.18934-ref29"><label>29</label><mixed-citation publication-type="other" xlink:type="simple">A. Sousa, D. A. Maria, R. G. Sousa and E. M. B. Sousa, “Synthesis and Characterization of Mesoporous Silica/ Poly(N-isopropylacrylamide) Functional Hybrid Useful for Drug Delivery,” Journal of Material Science, Vol. 45, No. 6, 2010, pp. 1478-1486. 
doi:10.1007/s10853-009-4106-3</mixed-citation></ref><ref id="scirp.18934-ref30"><label>30</label><mixed-citation publication-type="other" xlink:type="simple">T. Kokubo, et al., “Solutions Able to Reproduce in Vivo Surface-Structure Changes in Bioactive Glass-Ceramic A-W,” Journal of Biomedical Materials Research, Vol. 24, No. 6, 1990, pp. 721-734.  
doi:10.1002/jbm.820240607</mixed-citation></ref><ref id="scirp.18934-ref31"><label>31</label><mixed-citation publication-type="other" xlink:type="simple">T. Higuchi, “Mechanism of Sustained-Action Medication. Theoretical Analysis of Rate of Release of Solid Drugs Dispersed in Solid Matrices,” Journal of Pharmaceuticals Science, Vol. 52, No. 12, 1963, pp. 1145.  
doi:10.1002/jps.2600521210</mixed-citation></ref></ref-list></back></article>