Local Co-Delivery of Pancreatic Islets and Liposomal Clodronate Using Injectable Hydrogel to Prevent Acute Immune Reactions in a Type 1 Diabetes
The purpose of this study was to investigate the effect of locally delivered pancreatic islet with liposomal clodronate (Clodrosome®) as an immunoprotection agent for the treatment of type 1 diabetes.
The bio-distribution of liposomal clodronate in matrigel was checked by imaging analyzer. To verify the therapeutic efficacy of locally delivered islet with liposomal clodronate using injectable hydrogel, four groups of islet transplanted mice (n = 6 in each group) were prepared: 1) the islet group, 2) the islet-Clodrosome group, 3) the islet-Matrigel group, and 4) the islet-Matrigel-Clodrosome group. Immune cell migration and activation, and pro-inflammatory cytokine secretion was evaluated by immunohistochemistry staining and ELISA assay.
Cy5.5 labeled liposomes remained in the matrigel for over 7 days. The median survival time of transplanted islets (Islet-Matrigel-Clodrosome group) was significantly increased (>60 days), compared to other groups. Locally delivered liposomal clodronate in matrigel effectively inhibited the activation of macrophages, immune cell migration and activation, and pro-inflammatory cytokine secretion from macrophages.
Locally co-delivered pancreatic islets and liposomal clodronate using injectable hydrogel effectively cured type 1 diabetes. Especially, the inhibition of macrophage attack in the early stage after local delivery of islets was very important for the successful long-term survival of delivered islets.
KEY WORDSpancreatic islets liposomal clodronate injectable hydrogel local delivery macrophage depletion
Cluster of differentiation
Enzyme-linked immunosorbent assay
Roswell park memorial institute medium
Standard error of mean
Tumor necrosis factor-alpha
ACKNOWLEDGMENTS AND DISCLOSURES
This study was supported by grants from the Converging Research Center Program (grant no. 2012K001398) and Basic Science Research Program (grant no. 2010–0029407) funded through the National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology, and the Korea Health Technology R&D Project (grant no. HI12C1853) of the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea.
- 2.Elander L, Engstrom L, Ruud J, Mackerlova L, Jakobsson PJ, Engblom D, et al. Inducible prostaglandin E2 synthesis interacts in a temporally supplementary sequence with constitutive prostaglandin-synthesizing enzymes in creating the hypothalamic-pituitary-adrenal axis response to immune challenge. J Neurosci Off J Soc Neurosci. 2009;29(5):1404–13.CrossRefGoogle Scholar
- 6.Shahaf G, Moser H, Ozeri E, Mizrahi M, Abecassis A, Lewis EC. Alpha-1-antitrypsin gene delivery reduces inflammation, increases T-regulatory cell population size and prevents islet allograft rejection. Mol Med. 2011;9–10:1000–11.Google Scholar
- 7.Frith JC, Monkkonen J, Blackburn GM, Russell RG, Rogers MJ. Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5′-(beta, gamma-dichloromethylene) triphosphate, by mammalian cells in vitro. J Bone Miner Res Off J Am Soc Bone Miner Res. 1997;12(9):1358–67.CrossRefGoogle Scholar
- 8.Mönkkönen H, Törmälehto S, Asunmaa K, Niemi R, Auriola S, Vepsäläinen J, Mönkkönen J. Cellular uptake and metabolism of clodronate and its derivatives in Caco-2 cells: a possible correlation with bisphosphonate-induced gastrointestinal side-effects. In: Eur J Pharm Sci. 2003. p. 23–29.Google Scholar
- 9.Jordan MB, Van Rooijen N, Izui S, Kappler J, Marrack P. Liposomal clodronate as a novel agent for treating autoimmune hemolytic anemia in a mouse model. In: Blood. 2003. p. 594–601.Google Scholar
- 11.Phelps EA, Headen DM, Taylor WR, Thulé PM, García AJ. Vasculogenic bio-synthetic hydrogel for enhancement of pancreatic islet engraftment and function in type 1 diabetes. In: Biomaterials. 2013. p. 4602–4611.Google Scholar
- 12.Liao SW, Rawson J, Omori K, Ishiyama K, Mozhdehi D, Oancea AR, Ito T, Guan Z, Mullen Y. Maintaining functional islets through encapsulation in an injectable saccharide-peptide hydrogel. In: Biomaterials; 2013. p. 3984–3991.Google Scholar
- 13.Yang K-C, Wu C-C, Lin F-H, Qi Z, Kuo T-F, Cheng Y-H, Chen M-P, Sumi S. Chitosan/gelatin hydrogel as immunoisolative matrix for injectable bioartificial pancreas. In: Xenotransplantation. 2008. p. 407–416.Google Scholar
- 14.Lanza RP, Jackson R, Sullivan A, Ringeling J, McGrath C, Kühtreiber W, Chick WL. Xenotransplantation of cells using biodegradable microcapsules. In: Transplantation. 1999. p. 1105–1111.Google Scholar
- 15.Sun AM, O’Shea GM, Goosen MF. Injectable microencapsulated islet cells as a bioartificial pancreas. In: Appl Biochem Biotechnol. 1984. p. 87–99.Google Scholar