Original articles
Xianyan Qin, Yingying Xu, Xu Zhou, Tao Gong, Zhi-Rong Zhang, Yao Fu. An injectable micelle-hydrogel hybrid for localized and prolonged drug delivery in the management of renal fibrosis[J]. Acta Pharmaceutica Sinica B, 2021, 11(3): 835-847

An injectable micelle-hydrogel hybrid for localized and prolonged drug delivery in the management of renal fibrosis
Xianyan Qina,b, Yingying Xua, Xu Zhoua,c, Tao Gonga, Zhi-Rong Zhanga, Yao Fua
a Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China;
b Key Laboratory of Advanced Technologies of Materials, Ministry of Education and School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China;
c Sichuan Provincial Orthopedic Hospital, Chengdu 610041, China
Localized delivery, comparing to systemic drug administration, offers a unique alternative to enhance efficacy, lower dosage, and minimize systemic tissue toxicity by releasing therapeutics locally and specifically to the site of interests. Herein, a localized drug delivery platform (“plum-pudding” structure) with controlled release and long-acting features is developed through an injectable hydrogel (“pudding”) crosslinked via self-assembled triblock polymeric micelles (“plum”) to help reduce renal interstitial fibrosis. This strategy achieves controlled and prolonged release of model therapeutics in the kidney for up to three weeks in mice. Following a single injection, local treatments containing either anti-inflammatory small molecule celastrol or anti-TGFβ antibody effectively minimize inflammation while alleviating fibrosis via inhibiting NF-κB signaling pathway or neutralizing TGF-β1 locally.Importantly, the micelle-hydrogel hybrid based localized therapy shows enhanced efficacy without local or systemic toxicity, which may represent a clinically relevant delivery platform in the management of renal interstitial fibrosis.
Key words:    Hydrogel    “Plum-pudding&rdquo    structure    Localized therapy    Controlled release    Renal fibrosis    Inflammation    Celastrol    Anti-TGFβ antibody   
Received: 2020-06-23     Revised: 2020-09-04
DOI: 10.1016/j.apsb.2020.10.016
Funds: This work was supported by the National Natural Science Foundation of China (81773654, 81690261, 81503018), Sichuan Provincial Science and Technology Department (2019YJ0019, China), National Key Research and Development Plan of China (2017YFC1104601), Sichuan University Fund for Excellent Young Scholars (2017SCU04A23, China), and 111 Project (B18035, China).
Corresponding author: Yao Fu     Email:yfu4@scu.edu.cn
Author description:
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Xianyan Qin
Yingying Xu
Xu Zhou
Tao Gong
Zhi-Rong Zhang
Yao Fu

1. Wolinsky JB, Colson YL, Grinstaff MW. Local drug delivery strategies for cancer treatment: gels, nanoparticles, polymeric films, rods, and wafers. J Control Release 2012;159:14-26.
2. During MJ, Freese A, Deutch AY, Kibat PG, Sabel BA, Langer R, et al. Biochemical and behavioral recovery in a rodent model of Parkinsons-disease following stereotaxic implantation of dopaminecontaining liposomes. Exp Neurol 1992;115:193-9.
3. Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM. Polymeric systems for controlled drug release. Chem Rev 1999;99:3181-98.
4. Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 1995;345:1008-12.
5. Mathios D, Kim JE, Mangraviti A, Phallen J, Park CK, Jackson CM, et al. Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM. Sci Transl Med 2016;8. 370ra180.
6. Lin CC, Metters AT. Hydrogels in controlled release formulations: network design and mathematical modeling. Adv Drug Deliv Rev 2006;58:1379-408.
7. Yu L, Ding J. Injectable hydrogels as unique biomedical materials. Chem Soc Rev 2008;37:1473-81.
8. Gu D, O’Connor AJ, Qiao GGH, Ladewig K. Hydrogels with smart systems for delivery of hydrophobic drugs. Expert Opin Drug Deliv 2017;14:879-95.
9. Li JY, Mooney DJ. Designing hydrogels for controlled drug delivery. Nat Rev Mater 2016;1:16071.
10. Nanthakumar CB, Hatley RJD, Lemma S, Gauldie J, Marshall RP, Macdonald SJF. Dissecting fibrosis: therapeutic insights from the small-molecule toolbox. Nat Rev Drug Discov 2015;14:693-720.
11. Daniels CE, Lasky JA, Limper AH, Mieras K, Gabor E, Schroeder DR, et al. Imatinib treatment for idiopathic pulmonary fibrosis randomized placebo-controlled trial results. Am J Respir Crit Care Med 2010;181:604-10.
12. Prey S, Ezzedine K, Doussau A, Grandoulier AS, Barcat D, Chatelus E, et al. Imatinib mesylate in scleroderma-associated diffuse skin fibrosis: a phase II multicentre randomized double-blinded controlled trial. Br J Dermatol 2012;167:1138-44.
13. Shihab FS. Do we have a pill for renal fibrosis?. Clin J Am Soc Nephrol 2007;2:876-8.
14. Breyer MD, Susztak K. The next generation of therapeutics for chronic kidney disease. Nat Rev Drug Discov 2016;15:568-88.
15. Mackinnon M, Shurraw S, Akbari A, Knoll GA, Jaffey J, Clark HD. Combination therapy with an angiotensin receptor blocker and an ACE Inhibitor in proteinuric renal disease: a systematic review of the efficacy and safety data. Am J Kidney Dis 2006;48:8-20.
16. Zhang F, Liu H, Liu D, Liu Y, Li H, Tan X, et al. Effects of RAAS inhibitors in patients with kidney disease. Curr Hypertens Rep 2017; 19:72.
17. Kannaiyan R, Shanmugam MK, Sethi G. Molecular targets of celastrol derived from Thunder of God Vine: potential role in the treatment of inflammatory disorders and cancer. Cancer Lett 2011;303:9-20.
18. Cao X, Hu Y, Luo S, Wang Y, Gong T, Sun X, et al. Neutrophilmimicking therapeutic nanoparticles for targeted chemotherapy of pancreatic carcinoma. Acta Pharm Sin B 2019;9:575-89.
19. Hu Y, Chen X, Xu Y, Han X, Wang M, Gong T, et al. Hierarchical assembly of hyaluronan coated albumin nanoparticles for pancreatic cancer chemoimmunotherapy. Nanoscale 2019;11:16476-87.
20. Guo L, Luo S, Du Z, Zhou M, Li P, Fu Y, et al. Targeted delivery of celastrol to mesangial cells is effective against mesangioproliferative glomerulonephritis. Nat Commun 2017;8:878.
21. Wang S, Liu K, Wang X, He Q, Chen X. Toxic effects of celastrol on embryonic development of zebrafish (Danio rerio). Drug Chem Toxicol 2011;34:61-5.
22. Konieczny J, Jantas D, Lenda T, Domin H, Czarnecka A, Kuter K, et al. Lack of neuroprotective effect of celastrol under conditions of proteasome inhibition by lactacystin in in vitro and in vivo studies: implications for Parkinson’s disease. Neurotox Res 2014;26:255-73.
23. Lopez-Hernandez FJ, Lopez-Novoa JM. Role of TGF-beta in chronic kidney disease: an integration of tubular, glomerular and vascular effects. Cell Tissue Res 2012;347:141-54.
24. Qin X, Qiao W, Wang Y, Li T, Li X, Gong T, et al. An extracellular matrix-mimicking hydrogel for full thickness wound healing in diabetic mice. Macromol Biosci 2018;18:1800047.
25. Dong D, Li J, Cui M, Wang J, Zhou Y, Luo L, et al. Insitu "clickable" zwitterionic starch-based hydrogel for 3D cell encapsulation. ACS Appl Mater Interfaces 2016;8:4442-55.
26. Long D, Gong T, Zhang Z, Ding R, Fu Y. Preparation and evaluation of a phospholipid-based injectable gel for the long term delivery of leuprolide acetaterrh. Acta Pharm Sin B 2016;6:329-35.
27. Grigolo B, Lisignoli G, Piacentini A, Fiorini M, Gobbi P, Mazzotti G, et al. Evidence for redifferentiation of human chondrocytes grown on a hyaluronan-based biomaterial (HYAFF (R) 11): molecular, immunohistochemical and ultrastructural analysis. Biomaterials 2002;23: 1187-95.
28. Cao X, Luo J, Gong T, Zhang ZR, Sun X, Fu Y. Coencapsulated doxorubicin and bromotetrandrine lipid nanoemulsions in reversing multidrug resistance in breast cancer in vitro and in vivo. Mol Pharm 2015;12:274-86.
29. Burdick JA, Mason MN, Hinman AD, Thorne K, Anseth KS. Delivery of osteoinductive growth factors from degradable PEG hydrogels influences osteoblast differentiation and mineralization. J Control Release 2002;83:53-63.
30. Lamb CR, Cortellini S, Halfacree Z. Ultrasonography in the diagnosis and management of cats with ureteral obstruction. J Feline Med Surg 2018;20:15-22.
31. Rodell CB, Rai R, Faubel S, Burdick JA, Soranno DE. Local immunotherapy via delivery of interleukin-10 and transforming growth factor beta antagonist for treatment of chronic kidney disease. J Control Release 2015;206:131-9.
32. Soranno DE, Rodell CB, Altmann C, Duplantis J, AndresHernando A, Burdick JA, et al. Delivery of interleukin-10 via injectable hydrogels improves renal outcomes and reduces systemic inflammation following ischemic acute kidney injury in mice. Am J Physiol Renal Physiol 2016;311:F362-72.
33. Xu Y, Qin S, Niu Y, Gong T, Zhang Z, Fu Y. Effect of fluid shear stress on the internalization of kidney-targeted delivery systems in renal tubular epithelial cells. Acta Pharm Sin B 2020;10:680-92.
34. Cao X, Zhou X, Wang Y, Gong T, Zhang Z-R, Liu R, et al. Diblockand triblock-copolymer based mixed micelles with high tumor penetration in vitro and in vivo. J Mater Chem B 2016;4:3216-24.
35. Zhou X, Qin X, Gong T, Zhang Z-R, Fu Y. D-Fructose modification enhanced internalization of mixed micelles in breast cancer cells via GLUT5 transporters. Macromol Biosci 2017;17:1600529.
36. Revzin A, Russell RJ, Yadavalli VK, Koh WG, Deister C, Hile DD, et al. Fabrication of poly(ethylene glycol) hydrogel microstructures using photolithography. Langmuir 2001;17:5440-7.
37. Fu Y, Kao WJ. In situ forming poly(ethylene glycol)-based hydrogels via thiol-maleimide Michael-type addition. J Biomed Mater Res Part A 2011;98A:201-11.
38. Fu Y, Xu K, Zheng X, Giacomin AJ, Mix AW, Kao WJ. 3D cell entrapment in crosslinked thiolated gelatin-poly(ethylene glycol) diacrylate hydrogels. Biomaterials 2012;33:48-58.
39. Wang D, Xiong M, Chen Ca, Du L, Liu Z, Shi Y, et al. Legumain, an asparaginyl endopeptidase, mediates the effect of M2 macrophages on attenuating renal interstitial fibrosis in obstructive nephropathy. Kidney Int 2018;94:91-101.
40. Soranno DE, Lu HD, Weber HM, Rai R, Burdick JA. Immunotherapy with injectable hydrogels to treat obstructive nephropathy. J Biomed Mater Res Part A 2014;102:2173-80.
41. Hinz B. The extracellular matrix and transforming growth factor-beta 1: tale of a strained relationship. Matrix Biol 2015;47:54-65.
42. Nastase MV, Zeng-Brouwers J, Wygrecka M, Schaefer L. Targeting renal fibrosis: mechanisms and drug delivery systems. Adv Drug Deliv Rev 2018;129:295-307.
43. Ling H, Li XM, Jha S, Wang W, Karetskaya L, Pratt B, et al. Therapeutic role of TGF-beta-neutralizing antibody in mouse cyclosporin a nephropathy: morphologic improvement associated with functional preservation. J Am Soc Nephrol 2003;14:377-88.
44. MaLJ,JhaS,LingH,PozziA,LedbetterS,FogoAB.Divergenteffectsof low versus high dose anti-TGF-beta antibody in puromycin aminonucleoside nephropathy in rats. Kidney Int 2004;65:106-15.
45. Miyajima A, Chen J, Lawrence C, Ledbetter S, Soslow RA, Stern J, et al. Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney Int 2000;58: 2301-13.
46. Yang JW, Dai CS, Liu YH. A novel mechanism by which hepatocyte growth factor blocks tubular epithelial to mesenchymal transition. J Am Soc Nephrol 2005;16:68-78.
47. Zeisberg M. Bone morphogenic protein-7 and the kidney: current concepts and open questions. Nephrol Dial Transplant 2006;21:568-73.
48. Yu MA, Shin KS, Kim JH, Kim YI, Chung SS, Park SH, et al. HGF and BMP-7 ameliorate high glucose-induced epithelial-to-mesenchymal transition of peritoneal mesothelium. JAm Soc Nephrol2009;20:567-81.
49. Breyer MD, Susztak K. The next generation of therapeutics for chronic kidney disease. Nat Rev Drug Discov 2016;15:568-88.
50. Engel JE, Chade AR. Macrophage polarization in chronic kidney disease: a balancing act between renal recovery and decline?. Am J Physiol Renal Physiol 2019;317:F1409-13.
51. Ruffell B, Affara NI, Coussens LM. Differential macrophage programming in the tumor microenvironment. Trends Immunol 2012;33: 119-26.
52. Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol 2014;60:1090-6.
53. Benoit M, Desnues B, Mege JL. Macrophage polarization in bacterial infections. J Immunol 2008;181:3733-9.
54. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. Trends Immunol 2013;229:176-85.
55. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010;72:219-46.
56. Nikolic-Paterson DJ, Wang S, Lan HY. Macrophages promote renal fibrosis through direct and indirect mechanisms. Kidney Int Suppl 2014;4:34-8.
57. Munoz-Felix JM, Gonzalez-Nunez M, Martinez-Salgado C, LopezNovoa JM. TGF-beta/BMP proteins as therapeutic targets in renal fibrosis. Where have we arrived after 25 years of trials and tribulations?. Pharmacol Ther 2015;156:44-58.
58. Lan HY. Diverse roles of TGF-beta/smads in renal fibrosis and inflammation. Int J Biol Sci 2011;7:1056-67.
59. Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol 2016;12:325-38.
60. Meng XM, Nikolic-Paterson DJ, Lan HY. Inflammatory processes in renal fibrosis. Nat Rev Nephrol 2014;10:493-503.
61. Miguel Lopez-Novoa J, Angela Nieto M. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med 2009;1:303-14.
62. Zhou X, Yu R, Cao X, Zhang ZR, Deng L. Bio-mimicking nanoparticles for targeted therapy of malignant melanoma. J Biomed Nanotechnol 2019;15:993-1004.
63. Gong T, Zhang P, Deng C, Xiao Y, Gong T, Zhang Z. An effective and safe treatment strategy for rheumatoid arthritis based on human serum albumin and Kolliphor (R) HS 15. Nanomedicine 2019;14:2169-87.
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