Nilotinib-loaded gelatin methacryloyl microneedles patch for the treatment of cardiac dysfunction after myocardial infarction_Journal of Biomedical Engineering

Authors：

PENG Ningxin ,  XIE Jun

Department of Cardiology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing 210008, P. R. China;

Corresponding author：

XIE Jun, Email: xiejun@njglyy.com

Keywords：

Myocardial infarction; Cardiac dysfunction; Gelatin methacryloyl; Microneedles patch; Nilotinib

DOI：

10.7507/1001-5515.202208039

Video：

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The study aimed to evaluate the therapeutic effect of nilotinib-loaded biocompatible gelatin methacryloyl (GelMA) microneedles patch on cardiac dysfunction after myocardial infarction(MI), and provide a new clinical perspective of myocardial fibrosis therapies. The GelMA microneedles patches were attached to the epicardial surface of the infarct and peri-infarct zone in order to deliver the anti-fibrosis drug nilotinib on the 10th day after MI, when the scar had matured. Cardiac function and left ventricular remodeling were assessed by such as echocardiography, BNP (brain natriuretic peptide) and the heart weight/body weight ratio (HW/BW). Myocardial hypertrophy and fibrosis were examined by WGA (wheat germ agglutinin) staining, HE (hematoxylin-eosin staining) staining and Sirius Red staining. The results showed that the nilotinib-loaded microneedles patch could effectively attenuate fibrosis expansion in the peri-infarct zone and myocardial hypertrophy, prevent adverse ventricular remodeling and finally improve cardiac function. This treatment strategy is a beneficial attempt to correct the cardiac dysfunction after myocardial infarction, which is expected to become a new strategy to correct the cardiac dysfunction after MI. This is of great clinical significance for improving the long-term prognosis of MI patients.

Citation： PENG Ningxin, XIE Jun. Nilotinib-loaded gelatin methacryloyl microneedles patch for the treatment of cardiac dysfunction after myocardial infarction. Journal of Biomedical Engineering, 2023, 40(5): 996-1004. doi: 10.7507/1001-5515.202208039 Copy

1.	Sekulic M, Zacharias M, Medalion B. Ischemic cardiomyopathy and heart failure. Circ Heart Fail, 2019, 12(6): e006006.
2.	Bahit M C, Kochar A, Granger C B. Post-myocardial infarction heart failure. JACC Heart Fail, 2018, 6(3): 179-186.
3.	中国医师协会心血管内科医师分会, 中国心血管健康联盟, 心肌梗死后心力衰竭防治专家共识工作组. 2020心肌梗死后心力衰竭防治专家共识. 中国循环杂志, 2020, 35(12): 1166-1180.
4.	Frangogiannis N G. Pathophysiology of myocardial infarction. Comprehensive Physiology, 2015, 5(4): 1841.
5.	Humeres C, Frangogiannis N G. Fibroblasts in the infarcted, remodeling, and failing heart. JACC Basic Transl Sci, 2019, 4(3): 449-467.
6.	Talman V, Ruskoaho H. Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration. Cell Tissue Res, 2016, 365(3): 563-581.
7.	López B, Ravassa S, Moreno M U, et al. Diffuse myocardial fibrosis: mechanisms, diagnosis and therapeutic approaches. Nat Rev Cardiol, 2021, 18(7): 479-498.
8.	刘赟, 马骏, 卜东魁, 等. 心力衰竭治疗的研究进展. 中国介入心脏病学杂志, 2017, 25(12): 710-714.
9.	Sutton M G, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation, 2000, 101(25): 2981-2988.
10.	Zhang Q, Wang L, Wang S, et al. Signaling pathways and targeted therapy for myocardial infarction. Signal Transduct Target Ther, 2022, 7(1): 78.
11.	Damluji A A, van Diepen S, Katz J N, et al. Mechanical complications of acute myocardial infarction: a scientific statement from the American Heart Association. Circulation, 2021, 144(2): e16-e35.
12.	Gao X M, White D A, Dart A M, et al. Post-infarct cardiac rupture: recent insights on pathogenesis and therapeutic interventions. Pharmacol Ther, 2012, 134(2): 156-179.
13.	Lin X, Liu Y, Bai A, et al. A viscoelastic adhesive epicardial patch for treating myocardial infarction. Nat Biomed Eng, 2019, 3(8): 632-643.
14.	Tallquist M D. Cardiac fibroblast diversity. Annual Review of Physiology, 2020, 82: 63-78.
15.	Tallquist M D, Molkentin J D. Redefining the identity of cardiac fibroblasts. Nat Rev Cardiol, 2017, 14(8): 484-491.
16.	Prabhu S D, Frangogiannis N G. The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ Res, 2016, 119(1): 91-112.
17.	Marinelli B E, Costantini A, Mancini G, et al. Nilotinib treatment of patients affected by chronic graft-versus-host disease reduces collagen production and skin fibrosis by downmodulating the TGF-β and p-SMAD pathway. Biol Blood Marrow Transplant, 2020, 26(5): 823-834.
18.	Shaker M E, Salem H A, Shiha G E, et al. Nilotinib counteracts thioacetamide-induced hepatic oxidative stress and attenuates liver fibrosis progression. Fundam Clin Pharmacol, 2011, 25(2): 248-257.
19.	Iyoda M, Shibata T, Hirai Y, et al. Nilotinib attenuates renal injury and prolongs survival in chronic kidney disease. J Am Soc Nephrol, 2011, 22(8): 1486-1496.
20.	Distler J H, Distler O. Tyrosine kinase inhibitors for the treatment of fibrotic diseases such as systemic sclerosis: towards molecular targeted therapies. Ann Rheum Dis, 2010, 69 Suppl 1: i48-i51.
21.	Brazzelli V, Grasso V, Borroni G. Imatinib, dasatinib and nilotinib: a review of adverse cutaneous reactions with emphasis on our clinical experience. J Eur Acad Dermatol Venereol, 2013, 27(12): 1471-1480.
22.	Kim Y C, Park J H, Prausnitz M R. Microneedles for drug and vaccine delivery. Adv Drug Deliv Rev, 2012, 64(14): 1547-1568.
23.	Prausnitz M R, Langer R. Transdermal drug delivery. Nat Biotechnol, 2008, 26(11): 1261-1268.
24.	Stern D, Cui H. Crafting polymeric and peptidic hydrogels for improved wound healing. Adv Healthc Mater, 2019, 8(9): e1900104.
25.	Luo Z, Sun W, Fang J, et al. Biodegradable gelatin methacryloyl microneedles for transdermal drug delivery. Adv Healthc Mater, 2019, 8(3): e1801054.
26.	Yue K, Trujillo-de Santiago G, Alvarez M M, et al. Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels. Biomaterials, 2015, 73: 254-271.
27.	Algeciras L, Palanca A, Maestro D, et al. Epigenetic alterations of TGFβ and its main canonical signaling mediators in the context of cardiac fibrosis. J Mol Cell Cardiol, 2021, 159: 38-47.
28.	Ma Z G, Yuan Y P, Wu H M, et al. Cardiac fibrosis: new insights into the pathogenesis. Int J Biol Sci, 2018, 14(12): 1645-1657.
29.	Wu M, Xing Q, Duan H, et al. Suppression of NADPH oxidase 4 inhibits PM_2.5-induced cardiac fibrosis through ROS-P38 MAPK pathway. Sci Total Environ, 2022, 837: 155558.
30.	李轶男, 王萍, 陈晖. 冠状动脉微循环障碍对心肌纤维化的影响及研究现状. 中国介入心脏病学杂志, 2018, 26(8): 468-471.
31.	Khalil H, Kanisicak O, Prasad V, et al. Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest, 2017, 127(10): 3770-3783.
32.	Liu Y, Wang Z, Kwong S Q, et al. Inhibition of PDGF, TGF-β, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr-Abl tyrosine kinase antagonist Nilotinib. J Hepatol, 2011, 55(3): 612-625.

1. Sekulic M, Zacharias M, Medalion B. Ischemic cardiomyopathy and heart failure. Circ Heart Fail, 2019, 12(6): e006006.
2. Bahit M C, Kochar A, Granger C B. Post-myocardial infarction heart failure. JACC Heart Fail, 2018, 6(3): 179-186.
3. 中国医师协会心血管内科医师分会, 中国心血管健康联盟, 心肌梗死后心力衰竭防治专家共识工作组. 2020心肌梗死后心力衰竭防治专家共识. 中国循环杂志, 2020, 35(12): 1166-1180.
4. Frangogiannis N G. Pathophysiology of myocardial infarction. Comprehensive Physiology, 2015, 5(4): 1841.
5. Humeres C, Frangogiannis N G. Fibroblasts in the infarcted, remodeling, and failing heart. JACC Basic Transl Sci, 2019, 4(3): 449-467.
6. Talman V, Ruskoaho H. Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration. Cell Tissue Res, 2016, 365(3): 563-581.
7. López B, Ravassa S, Moreno M U, et al. Diffuse myocardial fibrosis: mechanisms, diagnosis and therapeutic approaches. Nat Rev Cardiol, 2021, 18(7): 479-498.
8. 刘赟, 马骏, 卜东魁, 等. 心力衰竭治疗的研究进展. 中国介入心脏病学杂志, 2017, 25(12): 710-714.
9. Sutton M G, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation, 2000, 101(25): 2981-2988.
10. Zhang Q, Wang L, Wang S, et al. Signaling pathways and targeted therapy for myocardial infarction. Signal Transduct Target Ther, 2022, 7(1): 78.
11. Damluji A A, van Diepen S, Katz J N, et al. Mechanical complications of acute myocardial infarction: a scientific statement from the American Heart Association. Circulation, 2021, 144(2): e16-e35.
12. Gao X M, White D A, Dart A M, et al. Post-infarct cardiac rupture: recent insights on pathogenesis and therapeutic interventions. Pharmacol Ther, 2012, 134(2): 156-179.
13. Lin X, Liu Y, Bai A, et al. A viscoelastic adhesive epicardial patch for treating myocardial infarction. Nat Biomed Eng, 2019, 3(8): 632-643.
14. Tallquist M D. Cardiac fibroblast diversity. Annual Review of Physiology, 2020, 82: 63-78.
15. Tallquist M D, Molkentin J D. Redefining the identity of cardiac fibroblasts. Nat Rev Cardiol, 2017, 14(8): 484-491.
16. Prabhu S D, Frangogiannis N G. The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ Res, 2016, 119(1): 91-112.
17. Marinelli B E, Costantini A, Mancini G, et al. Nilotinib treatment of patients affected by chronic graft-versus-host disease reduces collagen production and skin fibrosis by downmodulating the TGF-β and p-SMAD pathway. Biol Blood Marrow Transplant, 2020, 26(5): 823-834.
18. Shaker M E, Salem H A, Shiha G E, et al. Nilotinib counteracts thioacetamide-induced hepatic oxidative stress and attenuates liver fibrosis progression. Fundam Clin Pharmacol, 2011, 25(2): 248-257.
19. Iyoda M, Shibata T, Hirai Y, et al. Nilotinib attenuates renal injury and prolongs survival in chronic kidney disease. J Am Soc Nephrol, 2011, 22(8): 1486-1496.
20. Distler J H, Distler O. Tyrosine kinase inhibitors for the treatment of fibrotic diseases such as systemic sclerosis: towards molecular targeted therapies. Ann Rheum Dis, 2010, 69 Suppl 1: i48-i51.
21. Brazzelli V, Grasso V, Borroni G. Imatinib, dasatinib and nilotinib: a review of adverse cutaneous reactions with emphasis on our clinical experience. J Eur Acad Dermatol Venereol, 2013, 27(12): 1471-1480.
22. Kim Y C, Park J H, Prausnitz M R. Microneedles for drug and vaccine delivery. Adv Drug Deliv Rev, 2012, 64(14): 1547-1568.
23. Prausnitz M R, Langer R. Transdermal drug delivery. Nat Biotechnol, 2008, 26(11): 1261-1268.
24. Stern D, Cui H. Crafting polymeric and peptidic hydrogels for improved wound healing. Adv Healthc Mater, 2019, 8(9): e1900104.
25. Luo Z, Sun W, Fang J, et al. Biodegradable gelatin methacryloyl microneedles for transdermal drug delivery. Adv Healthc Mater, 2019, 8(3): e1801054.
26. Yue K, Trujillo-de Santiago G, Alvarez M M, et al. Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels. Biomaterials, 2015, 73: 254-271.
27. Algeciras L, Palanca A, Maestro D, et al. Epigenetic alterations of TGFβ and its main canonical signaling mediators in the context of cardiac fibrosis. J Mol Cell Cardiol, 2021, 159: 38-47.
28. Ma Z G, Yuan Y P, Wu H M, et al. Cardiac fibrosis: new insights into the pathogenesis. Int J Biol Sci, 2018, 14(12): 1645-1657.
29. Wu M, Xing Q, Duan H, et al. Suppression of NADPH oxidase 4 inhibits PM_2.5-induced cardiac fibrosis through ROS-P38 MAPK pathway. Sci Total Environ, 2022, 837: 155558.
30. 李轶男, 王萍, 陈晖. 冠状动脉微循环障碍对心肌纤维化的影响及研究现状. 中国介入心脏病学杂志, 2018, 26(8): 468-471.
31. Khalil H, Kanisicak O, Prasad V, et al. Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest, 2017, 127(10): 3770-3783.
32. Liu Y, Wang Z, Kwong S Q, et al. Inhibition of PDGF, TGF-β, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr-Abl tyrosine kinase antagonist Nilotinib. J Hepatol, 2011, 55(3): 612-625.

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