Abstract
Colon-targeted oral drug delivery systems comprising nanoparticles and microparticles have emerged as promising tools for the treatment of ulcerative colitis (UC) because they minimize side effects and maximize the local drug concentration. Dexamethasone sodium phosphate (DSP) is a potent anti-inflammatory glucocorticoid used for the treatment of UC. However, it remains a rather short-term treatment option owing to its side effects. In the present study, we developed the alginate gel encapsulating ionically bridged DSP-zinc-poly(lactic-co-glycolic acid) (PLGA) nanocomplex (DZP-NCs-in-microgel) for the oral local treatment of UC. The successful encapsulation of DSP-zinc-PLGA nanocomplex (DZP-NCs) in alginate microgel was confirmed by SEM imaging. The prepared gel released DZP-NCs in the stimulated intestinal fluid and dampened the release of DSP in the upper gastrointestinal tract. Furthermore, DZP-NCs-in-microgel alleviated colonic inflammation in a mouse model of dextran sodium sulfate-induced colitis by relieving clinical symptoms and histological marks. Our results suggest a novel approach for the oral colon-targeted delivery of dexamethasone sodium phosphate for the treatment of UC.
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References
Agüero L, Zaldivar-Silva D, Peña L, Dias ML (2017) Alginate microparticles as oral colon drug delivery device: a review. Carbohydr Polym 168:32–43. https://doi.org/10.1016/j.carbpol.2017.03.033
Bajpai S, Sharma S (2004) Investigation of swelling/degradation behaviour of alginate beads crosslinked with Ca2+ and Ba2+ ions. React Funct Polym 59:129–140. https://doi.org/10.1016/j.reactfunctpolym.2004.01.002
Bossa F, Latiano A, Rossi L, Magnani M, Palmieri O, Dallapiccola B, Serafini S, Damonte G, De Santo E, Andriulli A (2008) Erythrocyte-mediated delivery of dexamethasone in patients with mild-to- moderate ulcerative colitis, refractory to mesalamine: a randomized, controlled study. Am J Gastroenterol 103:2509–2516. https://doi.org/10.1111/j.1572-0241.2008.02103.x
Cao J, Naeem M, Noh J-K, Lee EH, Yoo J-W (2015) Dexamethasone phosphate-loaded folate-conjugated polymeric nanoparticles for selective delivery to activated macrophages and suppression of inflammatory responses. Macromol Res 23:485–492. https://doi.org/10.1007/s13233-015-3065-6
Chan L, Jin Y, Heng P (2002) Cross-linking mechanisms of calcium and zinc in production of alginate microspheres. Int J Pharm 242:255–258. https://doi.org/10.1016/S0378-5173(02)00169-2
Chaturvedi K, Ganguly K, More UA, Reddy KR, Dugge T, Naik B, Aminabhavi TM, Noolvi MN (2019) Sodium alginate in drug delivery and biomedical areas. Nat Polysacch Drug Deliv Biomed Appl. https://doi.org/10.1016/B978-0-12-817055-7.00003-0
Dai C, Zheng C-Q, Meng F-j, Zhou Z, Sang L-x, Jiang M (2013) VSL# 3 probiotics exerts the anti-inflammatory activity via PI3k/Akt and NF-κB pathway in rat model of DSS-induced colitis. Mol Cell Biochem 374:1–11. https://doi.org/10.1007/s11010-012-1488-3
Dupuis V, Laviole O, Potin-Gautier M, Castetbon A, Moya F (1992) Solubility and disintegration of zinc phosphate cement. Biomaterials 13:467–470. https://doi.org/10.1016/0142-9612(92)90168-N
Fernández-Clotet A, Castro-Poceiro J, Panés J (2018) Tofacitinib for the treatment of ulcerative colitis. Expert Rev Clin Immunol 14:881–892. https://doi.org/10.1080/1744666X.2018.1532291
Gómez-Gaete C, Tsapis N, Besnard M, Bochot A, Fattal E (2007) Encapsulation of dexamethasone into biodegradable polymeric nanoparticles. Int J Pharm 331:153–159. https://doi.org/10.1016/j.ijpharm.2006.11.028
Hasan N, Cao J, Lee J, Kim H, Yoo J-W (2021) Development of clindamycin-loaded alginate/pectin/hyaluronic acid composite hydrogel film for the treatment of MRSA-infected wounds. J Pharm Investig 51:597–610. https://doi.org/10.1007/s40005-021-00541-z
Ishihara T, Izumo N, Higaki M, Shimada E, Hagi T, Mine L, Ogawa Y, Mizushima Y (2005) Role of zinc in formulation of PLGA/PLA nanoparticles encapsulating betamethasone phosphate and its release profile. J Controll Release 105:68–76. https://doi.org/10.1016/j.jconrel.2005.02.026
Ishihara T, Takahashi M, Higaki M, Mizushima Y (2009) Efficient encapsulation of a water-soluble corticosteroid in biodegradable nanoparticles. Int J Pharm 365:200–205. https://doi.org/10.1016/j.ijpharm.2008.08.030
Iskandar L, Rojo L, Di Silvio L, Deb S (2019) The effect of chelation of sodium alginate with osteogenic ions, calcium, zinc, and strontium. J Biomater Appl 34:573–584. https://doi.org/10.1177/0885328219861904
Jeong S, Ju S, Park S, Jung Y (2021) 5-[(3-Carboxy-4-hydroxyphenyl) diazenyl] nicotinic acid, an azo-linked mesalazine-nicotinic acid conjugate, is a colon-targeted mutual prodrug against dextran sulfate sodium-induced colitis in mice. J Pharm Investig 51:317–325. https://doi.org/10.1007/s40005-021-00517-z
Khan HMW, Mehmood F, Khan N (2015) Optimal management of steroid-dependent ulcerative colitis. Clin Exp Gastroenterol 8:293. https://doi.org/10.2147/CEG.S57248
Kim J, Hlaing SP, Lee J, Saparbayeva A, Kim S, Hwang DS, Lee EH, Yoon I-S, Yun H, Kim M-S (2021) Exfoliated bentonite/alginate nanocomposite hydrogel enhances intestinal delivery of probiotics by resistance to gastric pH and on-demand disintegration. Carbohydr Polym 272:118462. https://doi.org/10.1016/j.carbpol.2021.118462
Ko JK, Auyeung KK (2014) Inflammatory bowel disease: etiology, pathogenesis and current therapy. Curr Pharm Des 20:1082–1096. https://doi.org/10.2174/13816128113199990416
Koelink PJ, Wildenberg ME, Stitt LW, Feagan BG, Koldijk M, Van ‘T, Wout AB, Atreya R, Vieth M, Brandse JF, Duijst S (2018) Development of reliable, valid and responsive scoring systems for endoscopy and histology in animal models for inflammatory bowel disease. J Crohns Colitis 12:794–803. https://doi.org/10.1093/ecco-jcc/jjy035
Lertpairod J, Tiyaboonchai W (2022) pH-sensitive beads containing curcumin loaded nanostructured lipid carriers for a colon targeted oral delivery system. J Pharm Investig 52:387–396. https://doi.org/10.1007/s40005-022-00572-0
Li M, Kaminskas LM, Marasini N (2021) Recent advances in nano/microparticle-based oral vaccines. J Pharm Investig 51:425–438. https://doi.org/10.1007/s40005-021-00537-9
Mahadevan U (2004) Medical treatment of ulcerative colitis. Clini Colon Rectal Surg 17:7–19. https://doi.org/10.1055/s-2004-823066
Makadia HK, Siegel SJ (2011) Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers 3:1377–1397. https://doi.org/10.3390/polym3031377
Makhlof A, Tozuka Y, Takeuchi H (2009) pH-Sensitive nanospheres for colon-specific drug delivery in experimentally induced colitis rat model. Eur J Pharm Biopharm 72:1–8. https://doi.org/10.1016/j.ejpb.2008.12.013
Murakami H, Matsuya Y, Matsuya S (1990) Dissolution mechanism of zinc phosphate dental cement in acetic and lactic acid buffers. Biomaterials 11:435–440. https://doi.org/10.1016/0142-9612(90)90101-U
Naeem M, Awan UA, Subhan F, Cao J, Hlaing SP, Lee J, Im E, Jung Y, Yoo J-W (2020) Advances in colon-targeted nano-drug delivery systems: challenges and solutions. Arch Pharm Res 43:153–169. https://doi.org/10.1007/s12272-020-01219-0
Oshi MA, Naeem M, Bae J, Kim J, Lee J, Hasan N, Kim W, Im E, Jung Y, Yoo J-W (2018) Colon-targeted dexamethasone microcrystals with pH-sensitive chitosan/alginate/Eudragit S multilayers for the treatment of inflammatory bowel disease. Carbohydr Polym 198:434–442. https://doi.org/10.1016/j.carbpol.2018.06.107
Park SC, Jeen YT (2015) Current and emerging biologics for ulcerative colitis. Gut Liver 9:18. https://doi.org/10.5009/gnl14226
Pasparakis G, Bouropoulos N (2006) Swelling studies and in vitro release of verapamil from calcium alginate and calcium alginate–chitosan beads. Interna J Pharm 323:34–42. https://doi.org/10.1016/j.ijpharm.2006.05.054
Pithadia AB, Jain S (2011) Treatment of inflammatory bowel disease (IBD). Pharmacol Rep 63:629–642. https://doi.org/10.1016/S1734-1140(11)70575-8
Sood A, Midha V, Sood N, Awasthi G (2002) A prospective, open-label trial assessing dexamethasone pulse therapy in moderate to severe ulcerative colitis. J Clin Gastroenterol 35:328–331. https://doi.org/10.1097/00004836-200210000-00009
Straccia MC, D’ayala GG, Romano I, Laurienzo P (2015) Novel zinc alginate hydrogels prepared by internal setting method with intrinsic antibacterial activity. Carbohydr Polym 125:103–112. https://doi.org/10.1016/j.carbpol.2015.03.010
Tran P, Park J-S (2022) Alginate-coated chitosan nanoparticles protect protein drugs from acid degradation in gastric media. J Pharm Investig. https://doi.org/10.1007/s40005-022-00574-y
Wang B, Tang Y, Oh Y, Lamb NW, Xia S, Ding Z, Chen B, Suarez MJ, Meng T, Kulkarni V (2019) Controlled release of dexamethasone sodium phosphate with biodegradable nanoparticles for preventing experimental corneal neovascularization. Nanomedicine 17:119–123. https://doi.org/10.1016/j.nano.2019.01.001
Xu C-T, Meng S-Y, Pan B-R (2004) Drug therapy for ulcerative colitis. World J Gastroenterol 10:2311–2317. https://doi.org/10.3748/wjg.v10.i16.2311
Zeb A, Gul M, Nguyen T-T-L, Maeng H-J (2022) Controlled release and targeted drug delivery with poly (lactic-co-glycolic acid) nanoparticles: reviewing two decades of research. J Pharm Investig. https://doi.org/10.1007/s40005-022-00584-w
Zhang M, Merlin D (2018) Nanoparticle-based oral drug delivery systems targeting the colon for treatment of ulcerative colitis. Inflamm Bowel Dis 24:1401–1415. https://doi.org/10.1093/ibd/izy123
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This research was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF) and was funded by the Ministry of Education (Grant Number: NRF-2022R1A2C2004340).
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Saparbayeva, A., Lee, J., Hlaing, S.P. et al. Ionically bridged dexamethasone sodium phosphate–zinc–PLGA nanocomplex in alginate microgel for the local treatment of ulcerative colitis. Arch. Pharm. Res. 46, 646–658 (2023). https://doi.org/10.1007/s12272-023-01456-z
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DOI: https://doi.org/10.1007/s12272-023-01456-z