Preparation of a Sustained Release Drug Delivery System for Dexamethasone by a Thermosensitive, In Situ Forming Hydrogel for Use in Differentiation of Dental Pulp
In situ forming delivery systems composed of block copolymers are attracting substantial attention due to their ease of use, biocompatibility, and biodegradability. In this study, the thermoresponsive triblock copolymer PLGA-PEG-PLGA was studied as a dexamethasone delivery system. Dexamethasone, a synthetic glucocorticoid, is used clinically to improve inflammation, pain, and the hyperemesis of chemotherapy, and it is applied experimentally as a differentiation factor in tissue engineering. PLGA-PEG-PLGA was synthesised under microwave irradiation for 5？min. The obtained copolymer was characterised to determine its structure and phase transition temperature. An in vitro release study was conducted for various copolymer structures and drug concentrations. The yield of the reaction and HNMR analysis confirmed the appropriateness of the microwave-assisted method for PLGA-PEG-PLGA synthesis. Phase transition temperature was affected by the drug molecule as well as by the copolymer concentration and structure. An in vitro release study demonstrated that release occurs mainly by diffusion and does not depend on the copolymer structure or dexamethasone concentration. 1. Introduction Pharmaceutical science has shown notable advancements in the development of novel drug delivery systems [1] in the form of microparticles [2, 3], nanoparticles [4, 5], and hydrogels [6, 7]. Most of these new carriers are made of polymers and particularly the biodegradable di- and tri block copolymers composed of hydrophobic and hydrophilic blocks, such as hydrophobic polycaprolactone [8, 9], polylactide [10, 11], poly propylene oxide [12], polylactide glycolide [13], and hydrophilic polyethylene glycol [14] and polyethylene oxide [15]. The copolymer structure allows the ready formation of nanomicelles and hydrogels due to physical crosslinking between hydrophobic sections [16]. These copolymers could also show intelligent behaviour with respect to phase transition and drug release profile [17]. Current smart delivery systems are focused on thermo-responsive and in situ gel-forming copolymers because of their ability to assume a gel form abruptly in response to a rise in temperature above the gelation temperature (the temperature at which the copolymer sol turns into a gel). This property makes a copolymer formulation injectable (sol) below body temperature and creates a sustained release system (gel) at body temperature [18–20]. PLGA-PEG-PLGA is a tri-block copolymer that consists of polyethylene glycol (PEG) and two polylactide glycolide (PLGA) blocks; the latter are composed of
References
[1]
Y. Zhang, H. F. Chan, and K. W. Leong, “Advanced materials and processing for drug delivery: the past and the future,” Advanced Drug Delivery Reviews, vol. 65, no. 1, pp. 104–120, 2013.
[2]
K. Bowey and R. J. Neufeld, “Systemic and mucosal delivery of drugs within polymeric microparticles produced by spray drying,” BioDrugs, vol. 24, no. 6, pp. 359–377, 2010.
[3]
W. Jiang, R. K. Gupta, M. C. Deshpande, and S. P. Schwendeman, “Biodegradable poly(lactic-co-glycolic acid) microparticles for injectable delivery of vaccine antigens,” Advanced Drug Delivery Reviews, vol. 57, no. 3, pp. 391–410, 2005.
[4]
C.-M. J. Hu and L. Zhang, “Nanoparticle-based combination therapy toward overcoming drug resistance in cancer,” Biochemical Pharmacology, vol. 83, no. 8, pp. 1104–1111, 2012.
[5]
D. F. Emerich and C. G. Thanos, “The pinpoint promise of nanoparticle-based drug delivery and molecular diagnosis,” Biomolecular Engineering, vol. 23, no. 4, pp. 171–184, 2006.
[6]
Y. Qiu and K. Park, “Environment-sensitive hydrogels for drug delivery,” Advanced Drug Delivery Reviews, vol. 53, no. 3, pp. 321–339, 2001.
[7]
T. R. Hoare and D. S. Kohane, “Hydrogels in drug delivery: progress and challenges,” Polymer, vol. 49, no. 8, pp. 1993–2007, 2008.
[8]
J. H. An, H. S. Kim, D. J. Chung, D. S. Lee, and S. Kim, “Thermal behaviour of poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) tri-block copolymers,” Journal of Materials Science, vol. 36, no. 3, pp. 715–722, 2001.
[9]
E. Khodaverdi, A. Golmohammadian, S. A. Mohajeri, G. Zohuri, F. S. Mirzazadeh Tekie, and F. Hadizadeh, “Biodegradable in situ gel-forming controlled drug delivery system based on thermosensitive poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) hydrogel,” ISRN Pharmaceutics, vol. 2012, Article ID 976879, 7 pages, 2012.
[10]
S. A. Hagan, A. G. A. Coombes, M. C. Garnett et al., “Polylactide-poly(ethylene glycol) copolymers as drug delivery systems. 1. Characterization of water dispersible micelle-forming systems,” Langmuir, vol. 12, no. 9, pp. 2153–2161, 1996.
[11]
L. Chen, Z. Xie, J. Hu, X. Chen, and X. Jing, “Enantiomeric PLA-PEG block copolymers and their stereocomplex micelles used as rifampin delivery,” Journal of Nanoparticle Research, vol. 9, no. 5, pp. 777–785, 2007.
[12]
I. Goldmints, J. F. Holzwarth, K. A. Smith, and T. A. Hatton, “Micellar dynamics in aqueous solutions of PEO-PPO-PEO block copolymers,” Langmuir, vol. 13, no. 23, pp. 6130–6133, 1997.
[13]
B. Jeong, Y. H. Bae, and S. W. Kim, “Biodegradable thermosensitive micelles of PEG-PLGA-PEG triblock copolymers,” Colloids and Surfaces B, vol. 16, no. 1-4, pp. 185–193, 1999.
[14]
F. Ahmed and D. E. Discher, “Self-porating polymersomes of PEG-PLA and PEG-PCL: hydrolysis-triggered controlled release vesicles,” Journal of Controlled Release, vol. 96, no. 1, pp. 37–53, 2004.
[15]
S. Y. Park, D. K. Han, and S. C. Kim, “Synthesis and characterization of star-shaped PLLA-PEO block copolymers with temperature-sensitive sol-gel transition behavior,” Macromolecules, vol. 34, no. 26, pp. 8821–8824, 2001.
[16]
N. Kumar, M. N. V. Ravikumar, and A. J. Domb, “Biodegradable block copolymers,” Advanced Drug Delivery Reviews, vol. 53, no. 1, pp. 23–44, 2001.
[17]
A. K. Bajpai, S. K. Shukla, S. Bhanu, and S. Kankane, “Responsive polymers in controlled drug delivery,” Progress in Polymer Science, vol. 33, no. 11, pp. 1088–1118, 2008.
[18]
A. Hatefi and B. Amsden, “Biodegradable injectable in situ forming drug delivery systems,” Journal of Controlled Release, vol. 80, no. 1-3, pp. 9–28, 2002.
[19]
C. B. Packhaeuser, J. Schnieders, C. G. Oster, and T. Kissel, “In situ forming parenteral drug delivery systems: an overview,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 58, no. 2, pp. 445–455, 2004.
[20]
K. S. Anseth, A. T. Metters, S. J. Bryant, P. J. Martens, J. H. Elisseeff, and C. N. Bowman, “In situ forming degradable networks and their application in tissue engineering and drug delivery,” Journal of Controlled Release, vol. 78, no. 1-3, pp. 199–209, 2002.
[21]
G. M. Zentner, R. Rathi, C. Shih et al., “Biodegradable block copolymers for delivery of proteins and water-insoluble drugs,” Journal of Controlled Release, vol. 72, no. 1-3, pp. 203–215, 2001.
[22]
M. Qiao, D. Chen, X. Ma, and Y. Liu, “Injectable biodegradable temperature-responsive PLGA-PEG-PLGA copolymers: synthesis and effect of copolymer composition on the drug release from the copolymer-based hydrogels,” International Journal of Pharmaceutics, vol. 294, no. 1-2, pp. 103–112, 2005.
[23]
S. Chen and J. Singh, “Controlled release of growth hormone from thermosensitive triblock copolymer systems: in vitro and in vivo evaluation,” International Journal of Pharmaceutics, vol. 352, no. 1-2, pp. 58–65, 2008.
[24]
M. Qiao, D. Chen, X. Ma, and H. Hu, “Sustained release of bee venom peptide from biodegradable thermosensitive PLGA-PEG-PLGA triblock copolymer-based hydrogels in vitro,” Die Pharmazie, vol. 61, no. 3, pp. 199–202, 2006.
[25]
Y. J. Kim, S. Choi, J. J. Koh, M. Lee, K. S. Ko, and S. W. Kim, “Controlled release of insulin from injectable biodegradable triblock copolymer,” Pharmaceutical Research, vol. 18, no. 4, pp. 548–550, 2001.
[26]
E. Khodaverdi, F. S. M. Tekie, S. A. Mohajeri, F. Ganji, G. Zohuri, and F. Hadizadeh, “Preparation and investigation of sustained drug delivery systems using an injectable, thermosensitive, in situ forming hydrogel composed of PLGA-PEG-PLGA,” AAPS PharmSciTech, vol. 13, no. 2, pp. 590–600, 2012.
[27]
S. Chen, R. Pieper, D. C. Webster, and J. Singh, “Triblock copolymers: synthesis, characterization, and delivery of a model protein,” International Journal of Pharmaceutics, vol. 288, no. 2, pp. 207–218, 2005.
[28]
L. Yu, Z. Zhang, and J. Ding, “Influence of la and GA sequence in the PLGA block on the properties of thermogelling PLGA-PEG-PLGA block copolymers,” Biomacromolecules, vol. 12, no. 4, pp. 1290–1297, 2011.
[29]
E. Khodaverdi, F. Hadizadeh, F. S. M. Tekie, A. Jalali, S. A. Mohajeri, and F. Ganji, “Preparation and analysis of a sustained drug delivery system by PLGA-PEG-PLGA triblock copolymers,” Polymer Bulletin, vol. 69, no. 4, pp. 429–438, 2012.
[30]
M. N. Silverman and E. M. Sternberg, “Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction,” Annals of the New York Academy of Sciences, vol. 1261, no. 1, pp. 55–63, 2012.
[31]
N. Rohleder, J. M. Wolf, and O. T. Wolf, “Glucocorticoid sensitivity of cognitive and inflammatory processes in depression and posttraumatic stress disorder,” Neuroscience and Biobehavioral Reviews, vol. 35, no. 1, pp. 104–114, 2010.
[32]
M. Markman, V. Sheidler, and D. S. Ettinger, “Antiemetic efficacy of dexamethasone. Randomized, double-blind, crossover study with prochlorperazine in patients receiving cancer chemotherapy,” The New England Journal of Medicine, vol. 311, no. 9, pp. 549–552, 1984.
[33]
S. M. Grunberg, “Antiemetic activity of corticosteroids in patients receiving cancer chemotherapy: dosing, efficacy, and tolerability analysis,” Annals of Oncology, vol. 18, no. 2, pp. 233–240, 2007.
[34]
R. E. Coleman, “Glucocorticoids in cancer therapy,” Biotherapy, vol. 4, no. 1, pp. 37–44, 1992.
[35]
I. Herr, E. Ucur, K. Herzer et al., “Glucocorticoid cotreatment induces apoptosis resistance toward cancer therapy in carcinomas,” Cancer Research, vol. 63, no. 12, pp. 3112–3120, 2003.
[36]
D. L. Deifenderfer, A. M. Osyczka, G. C. Reilly, and P. S. Leboy, “BMP responsiveness in human mesenchymal stem cells,” Connective Tissue Research, vol. 44, no. 1, pp. 305–311, 2003.
[37]
Y. Ogata, M. Yamauchi, R. H. Kim, J. J. Li, L. P. Freedman, and J. Sodek, “Glucocorticoid regulation of bone sialoprotein (BSP) gene expression—identification of a glucocorticoid response element in the bone sialoprotein gene promoter,” European Journal of Biochemistry, vol. 230, no. 1, pp. 183–192, 1995.
[38]
A. Martins, A. R. C. Duarte, S. Faria, A. P. Marques, R. L. Reis, and N. M. Neves, “Osteogenic induction of hBMSCs by electrospun scaffolds with dexamethasone release functionality,” Biomaterials, vol. 31, no. 22, pp. 5875–5885, 2010.
[39]
S. Srisawasdi and P. Pavasant, “Different roles of dexamethasone on transforming growth factor-β1-induced fibronectin and nerve growth factor expression in dental pulp cells,” Journal of Endodontics, vol. 33, no. 9, pp. 1057–1060, 2007.
[40]
B. Alliot-Licht, G. Bluteau, D. Magne et al., “Dexamethasone stimulates differentiation of odontoblast-like cells in human dental pulp cultures,” Cell and Tissue Research, vol. 321, no. 3, pp. 391–400, 2005.
[41]
Y. N. Kalia and R. H. Guy, “Modeling transdermal drug release,” Advanced Drug Delivery Reviews, vol. 48, no. 2-3, pp. 159–172, 2001.
[42]
A. Sosnik, G. Gotelli, and G. A. Abraham, “Microwave-assisted polymer synthesis (MAPS) as a tool in biomaterials science: how new and how powerful,” Progress in Polymer Science, vol. 36, no. 8, pp. 1050–1078, 2011.
[43]
A. A. Ghahremankhani, F. Dorkoosh, and R. Dinarvand, “PLGA-PEG-PLGA tri-block copolymers as in situ gel-forming peptide delivery system: effect of formulation properties on peptide release,” Pharmaceutical Development and Technology, vol. 13, no. 1, pp. 49–55, 2008.
[44]
B. Amsden, “Solute diffusion within hydrogels. Mechanisms and models,” Macromolecules, vol. 31, no. 23, pp. 8382–8395, 1998.
