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AAPS PharmSciTech

, 20:110 | Cite as

Nanofiber-Mediated Sustained Delivery of Triiodothyronine: Role in Angiogenesis

  • Aishwarya Satish
  • Purna Sai KorrapatiEmail author
Research Article

Abstract

Angiogenesis is a vital component of the orchestrated wound healing cascade and tissue regeneration process, which has a therapeutic prominence in treatment of ischemic vascular diseases and certain cardiac conditions. Based on its eminence, several strategies using growth factors have been studied to initiate angiogenesis. However, growth factors are expensive and have short half-life. In this work, sustained release of triiodothyronine, which plays a crucial role in stimulating growth factors and other signaling pathways that are instrumental in initiating angiogenesis, has been attempted through electrospun polycaprolactone nanofibers. This delivery system enabled the slow and sustained delivery of triiodothyronine into the micro-environment, reducing seepage of excess into systemic circulation and eliminating the necessity of repeated dosage forms. It was observed that triiodothyronine-incorporated nanofibers exhibited favorable interaction with cells (phalloidin staining of actin filaments) and also enhanced the rate of endothelial proliferation, migration, and adhesion. The angiogenic potential of these nanofibers was further corroborated through chorioallantoic membrane and rat aortic ring assay (demonstrating cell sprouting area of 3.3 ± 0.71 mm2 compared to 1.2 ± 0.01 mm2 in control). The nanofiber matrix thus fabricated demonstrated a vibrant therapeutic potential to induce angiogenesis. Triiodothyronine also plays a significant role in wound healing independent of initiating angiogenesis. This further substantiates the positive impact of this delivery system as a dressing material for chronic wound therapeutics, ischemic vascular diseases, and certain cardiac conditions.

Key Words

triiodothyronine angiogenesis nanofibers polycaprolactone wound healing 

Notes

Acknowledgements

The authors are grateful to the Director, CSIR – CLRI for his constant support. The research is carried out as a part of Ph.D. work registered in the University of Madras, Chennai. The first author would like to acknowledge the DST-INSPIRE programme, New Delhi for the research fellowship (IF130876).

References

  1. 1.
    Gurtner G, Werner S, Barrandon Y, Longaker M. Wound repair and regeneration. Nature. 2008;453(7193):314–21.PubMedCrossRefGoogle Scholar
  2. 2.
    Diegelmann RF, Evans MC. Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci. 2004;9:283–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Battegay EJ. Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects. J Mol Med. 1995;73(7):333–46.CrossRefGoogle Scholar
  4. 4.
    Davies NH, Schmidt C, Bezuidenhout D, Zilla P. Sustaining neovascularization of a scaffold through staged release of vascular endothelial growth factor-a and platelet-derived growth factor-BB. Tissue Eng Part A. 2012;18(1–2):26–34.PubMedCrossRefGoogle Scholar
  5. 5.
    Li Z, Qu T, Ding C, Ma C, Sun H, Li S, et al. Injectable gelatin derivative hydrogels with sustained vascular endothelial growth factor release for induced angiogenesis. Acta Biomater. 2015;13:88–100.PubMedCrossRefGoogle Scholar
  6. 6.
    Lai HJ, Kuan CH, Wu HC, Tsai JC, Chen TM, Hsieh DJ, et al. Tailored design of electrospun composite nanofibers with staged release of multiple angiogenic growth factors for chronic wound healing. Acta Biomater. 2014;10(10):4156–66.PubMedCrossRefGoogle Scholar
  7. 7.
    Bai Y, Yin G, Huang Z, Liao X, Chen X, Yao Y, et al. Localized delivery of growth factors for angiogenesis and bone formation in tissue engineering. Int Immunopharmacol. 2013;16(2):214–23.PubMedCrossRefGoogle Scholar
  8. 8.
    Zigdon-giladi H, Khutaba A, Elimelech R, Machtei EE, Srouji S. VEGF release from a polymeric nanofiber scaffold for improved angiogenesis. J Biomed Mater Res - Part A. 2017;105 A:2712–21.CrossRefGoogle Scholar
  9. 9.
    Choi DH, Subbiah R, Kim IH, Han DK, Park K. Dual growth factor delivery using biocompatible core-shell microcapsules for angiogenesis. Small. 2013;9(20):3468–76.PubMedCrossRefGoogle Scholar
  10. 10.
    Davis PJ, Davis FB, Mousa SA. Thyroid hormone-induced angiogenesis. Curr Cardiol Rev. 2009;5:12–6.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Rajagopalan V, Zhang Y, Pol C, Costello C, Seitter S, Lehto A, et al. Modified low-dose triiodo-L-thyronine therapy safely improves function following myocardial ischemia-reperfusion injury. Front Physiol. 2017;8:1–11.CrossRefGoogle Scholar
  12. 12.
    Wang W, Guan H, Fang W, Zhang K, Gerdes AM, Iervasi G, et al. Free triiodothyronine level correlates with myocardial injury and prognosis in idiopathic dilated cardiomyopathy : evidence from cardiac MRI and SPECT/PET imaging. Sci Rep. 2016;6:1–9.CrossRefGoogle Scholar
  13. 13.
    Luidens MK, Mousa SA, Davis FB, Lin H, Davis PJ. Thyroid hormone and angiogenesis. Vasc Pharmacol. 2010;52:142–5.CrossRefGoogle Scholar
  14. 14.
    Tomanek RJ, Doty MK, Sandra A. Early coronary angiogenesis in response to thyroxine. Circ Res. 1998;82:587–93.PubMedCrossRefGoogle Scholar
  15. 15.
    Davis FB, Mousa SA, Connor LO, Mohamed S, Lin H, Cao HJ, et al. Proangiogenic action of thyroid hormone is fibroblast growth factor – dependent and is initiated at the cell surface. Circ Res. 2004;94:1500–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Biro S, Yu Z-X, Fu Y-M, Smale G, Sasse J, Sanchez J, et al. Expression and subcellular distribution of basic fibroblast growth factor are regulated during migration of endothelial cells. Circ Res. 1993;74:485–94.CrossRefGoogle Scholar
  17. 17.
    Yanagisawa-Miwa A, Uchida Y, Nakamura F, Tomaru T, Kido H, Kamijo T, et al. Salvage of infarcted myocardium by angiogenic action of basic fibroblast growth factor. Science. 1992;257:1401–3.PubMedCrossRefGoogle Scholar
  18. 18.
    Kassem R, Liberty Z, Babaev M, Trau H, Cohen O. Harnessing the skin-thyroid connection for wound healing: a prospective controlled trial in guinea pigs. Clin Exp Dermatol. 2012;37(8):850–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Satish A, Korrapati PS. Fabrication of a triiodothyronine incorporated nanofibrous biomaterial: its implications on wound healing. RSC Adv. 2015;5:83773–80.CrossRefGoogle Scholar
  20. 20.
    Safer JD, Fraser LM, Ray S, Holick MF. Topical triiodothyronine stimulates epidermal proliferation , dermal thickening , and hair growth in mice and rats. Thyroid. 2001;11(8):717–24.PubMedCrossRefGoogle Scholar
  21. 21.
    Safer JD. Thyroid hormone and wound healing. J Thyroid Res. 2013;2013:1–5.CrossRefGoogle Scholar
  22. 22.
    Lin Y, Sun Z. Thyroid hormone potentiates insulin signaling and attenuates hyperglycemia and insulin resistance in a mouse model of type 2 diabetes. Br J Pharmacol. 2011;162(3):597–610.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Ghosal K, Manakhov A, Zajíčková L, Thomas S. Structural and surface compatibility study of modified electrospun poly(ε-caprolactone) (PCL) composites for skin tissue engineering. AAPS PharmSciTech. 2017;18:72–81.PubMedCrossRefGoogle Scholar
  24. 24.
    Solano AGR, de Fátima Pereira A, Pinto FCH, Ferreira LGR, de Oliveira Barbosa LA, Fialho SL, et al. Development and evaluation of sustained-release etoposide-loaded poly(ε-caprolactone) implants. AAPS PharmSciTech. 2013;14(2):890–900.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Mofidfar M, Wang J, Long L, Hager CL, Vareechon C, Pearlman E, et al. Polymeric nanofiber/antifungal formulations using a novel co-extrusion approach. AAPS PharmSciTech. 2017;18(6):1917–24.PubMedCrossRefGoogle Scholar
  26. 26.
    Satish A, Korrapati PS. Tailored release of triiodothyronine and retinoic acid from a spatio-temporally fabricated nanofiber composite instigating neuronal differentiation. Nanoscale. 2017;9:14565–80.PubMedCrossRefGoogle Scholar
  27. 27.
    Madhaiyan K, Sridhar R, Sundarrajan S, Venugopal JR, Ramakrishna S. Vitamin B12 loaded polycaprolactone nanofibers: a novel transdermal route for the water soluble energy supplement delivery. Int J Pharm. 2013;444(1–2):70–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Janani I, Lakra R, Kiran MS, Korrapati PS. Selectivity and sensitivity of molybdenum oxide-polycaprolactone nano fiber composites on skin cancer: preliminary in-vitro and in-vivo implications. J Trace Elem Med Biol. 2018;49:60–71.PubMedCrossRefGoogle Scholar
  29. 29.
    Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65(1–2):55–63.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Chandrakasan G, Torchia DA, Piez KA. Preparation of intact monomeric collagen from rat tail tendon and skin and the structure of the nonhelical ends in solution. J Biol Chem. 1976;251(19):6062–7.PubMedGoogle Scholar
  31. 31.
    Rajan N, Habermehl J, Cote M, Doillon CJ, Mantovani D. Preparation of ready-to-use, storable and reconstituted type I collagen from rat tail tendon for tissue engineering applications. Nat Protoc. 2006;1(6):2753–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Baker M, Robinson SD, Lechertier T, Barber PR, Tavora B, Amico GD, et al. Use of the mouse aortic ring assay to study angiogenesis. Nat Protoc. 2011;7(1):89–104.PubMedCrossRefGoogle Scholar
  33. 33.
    Krishnaswamy VR, Balaguru UM, Chatterjee S, Korrapati PS. Dermatopontin augments angiogenesis and modulates the expression of transforming growth factor beta 1 and integrin alpha 3 beta 1 in endothelial. Eur J Cell Biol. 2017;96(3):266–75.PubMedCrossRefGoogle Scholar
  34. 34.
    Paneva D, Bougard F, Manolova N, Dubois P, Rashkov I. Novel electrospun poly(ε-caprolactone)-based bicomponent nanofibers possessing surface enriched in tertiary amino groups. Eur Polym J. 2008;44(3):566–78.CrossRefGoogle Scholar
  35. 35.
    Marsac PJ, Li T, Taylor LS. Estimation of drug-polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters. Pharm Res. 2009;26(1):139–51.PubMedCrossRefGoogle Scholar
  36. 36.
    Yoshida K, Aiyama S, Uchida M, Kurabuchi S. Role of thyroid hormone in the initiation of EGF (epidermal growth factor) expression in the sublingual gland of the postnatal mouse. Anat Rec - Part A. 2005;284:585–93.CrossRefGoogle Scholar
  37. 37.
    Lin H, Sun M, Tang H, Lin C, Luidens MK, Mousa SA, et al. L-thyroxine vs. 3,5,3′-triiodo-L-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Am J Physiol Physiol. 2009;296:C980–91.CrossRefGoogle Scholar
  38. 38.
    Antonini D, Sibilio A, Dentice M, Missero C. An intimate relationship between thyroid hormone and skin: regulation of gene expression. Front Endocrinol (Lausanne). 2013;4:1–9.CrossRefGoogle Scholar
  39. 39.
    Solano AGR, de Fátima Pereira A, de Faria LGA, Fialho SL, de Oliveira Patricio PS, da Silva-Cunha A, et al. Etoposide-loaded poly(lactic-co-glycolic acid) intravitreal implants: in vitro and in vivo evaluation. AAPS PharmSciTech. 2018;19(4):1652–61.PubMedCrossRefGoogle Scholar
  40. 40.
    Deryugina EI, Quigley JP. Chapter 2 Chick embryo chorioallantoic membrane models to quantify angiogenesis induced by inflammatory and tumor cells or purified effector molecules. Methods Enzymol. 2008;444:21–41.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Schlenker EH, Hora M, Liu Y, Redetzke RA, Morkin E, Gerdes AM. Effects of thyroidectomy, T4, and DITPA replacement on brain blood vessel density in adult rats. AJP Regul Integr Comp Physiol. 2008;294(5):R1504–9.CrossRefGoogle Scholar
  42. 42.
    Liu X, Zheng N, Shi Y, Yuan J, Li L. Thyroid hormone induced angiogenesis through the integrin alpha v beta 3/protein kinase D/histone deacetylase 5 signaling pathway. J Mol Endocrinol. 2014;52:245–54.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  1. 1.Biological Materials LaboratoryCSIR - Central Leather Research InstituteChennaiIndia

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