The metaiodobenzylguanidine (MIBG) radiopharmaceutical, an analogue of norepinephrine, has been used to diagnose certain diseases in the cardiovascular system when radiolabeled with 123I. This radiopharmaceutical can also be used to treat tumors, such as neuroblastomas and pheochromocytomas, when radiolabeled with 131I. 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.
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 123I, 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 131I [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].
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 m2/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].
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].
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 [
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.
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.
SBA-15 silica was prepared according to Zhao [
The hybrid was prepared using the following procedure [
The FTIR measurements were conducted with an ABB Bomen model MB102 spectrophotometer within the range of 4000 - 400 cm–1. The FTIR spectra were recorded at room temperature using KBr pellets and a resolution of 4 cm–1 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 ® (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 Å, while the angle scattering 2θ ranged from 0˚ to 5˚.
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 µg·mL–1) 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) [
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).
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·mL–1). 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.
All experiments were performed in triplicate and expressed as the mean ± 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.
The monomer characteristic bands (nC=C 1620 cm–1; dCH2 = 1409 cm–1; dH2C=C- 1305 and 1325 cm–1; dvinyl group at 990 and 916 cm–1) were not present in the hybrid sample spectra, as can be seen in the scale-expanded FTIR spectrum in the 1800 - 900 cm–1 region (