Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Targeting protein and peptide therapeutics to the heart via tannic acid modification

Nature Biomedical Engineering volume 2, pages 304–317 (2018)Cite this article

Subjects

Abstract

Systemic injection into blood vessels is the most common method of drug administration. However, targeting drugs to the heart is challenging, owing to its dynamic mechanical motions and large cardiac output. Here, we show that the modification of protein and peptide therapeutics with tannic acid—a flavonoid found in plants that adheres to extracellular matrices, elastins and collagens—improves their ability to specifically target heart tissue. Tannic-acid-modified (TANNylated) proteins do not adsorb on endothelial glycocalyx layers in blood vessels, yet they penetrate the endothelium to thermodynamically bind to myocardium extracellular matrix before being internalized by myoblasts. In a rat model of myocardial ischaemia-reperfusion injury, TANNylated basic fibroblast growth factor significantly reduced infarct size and increased cardiac function. TANNylation of systemically injected therapeutic proteins, peptides or viruses may enhance the treatment of heart diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Preparation process of TANNylated GFP.
Fig. 2: Heart-targeting and heart accumulation effects of protein TANNylation.
Fig. 3: Heart-targeting mechanism: permeation and phenolic retention to ECMs for cellular uptake.
Fig. 4: TANNylation of therapeutic peptides and AAV9, and its heart-targeting effect.
Fig. 5: Effects of TANNylated GFP on rat MAPs.
Fig. 6: Effects of TANNylated GFP on cardiac function using P–V loop analysis.
Fig. 7: Therapeutic effects of TANNylated bFGF in MIR models.

Similar content being viewed by others

References

  1. Maeda, H., Nakamura, H. & Fang, J. The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv. Drug Deliv. Rev. 65, 71–79 (2013).

    Article  PubMed  CAS  Google Scholar 

  2. Rozema, D. B. et al. Dynamic polyconjugates for targeted in vivo delivery of siRNA to hepatocytes. Proc. Natl Acad. Sci. USA 104, 12982–12987 (2007).

    Article  PubMed  CAS  Google Scholar 

  3. Akinc, A. et al. Development of lipidoid–siRNA formulations for systemic delivery to the liver. Mol. Ther. 17, 872–879 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Kaczmarek, J. C. et al. Polymer–lipid nanoparticles for systemic delivery of mRNA to the lungs. Angew. Chem. Int. Ed. 128, 14012–14016 (2016).

    Article  Google Scholar 

  5. Khan, O. F. et al. Dendrimer-inspired nanomaterials for the in vivo delivery of siRNA to lung vasculature. Nano Lett. 15, 3008–3016 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Shimizu, T., Yamato, M., Kikuchi, A. & Okano, T. Cell sheet engineering for myocardial tissue reconstruction. Biomaterials 24, 2309–2316 (2003).

    Article  PubMed  CAS  Google Scholar 

  7. Nelson, D. M., Ma, Z., Fujimoto, K. L., Hashizume, R. & Wagner, W. R. Intra-myocardial biomaterial injection therapy in the treatment of heart failure: materials, outcomes and challenges. Acta Biomater. 7, 1–15 (2011).

    Article  PubMed  CAS  Google Scholar 

  8. Hamdi, H. et al. Cell delivery: intramyocardial injections or epicardial deposition? A head-to-head comparison. Ann. Thorac. Surg. 87, 1196–1203 (2009).

    Article  PubMed  Google Scholar 

  9. Miyagi, Y. et al. Biodegradable collagen patch with covalently immobilized VEGF for myocardial repair. Biomaterials 32, 1280–1290 (2011).

    Article  PubMed  CAS  Google Scholar 

  10. Nelson, D. M. et al. Intramyocardial injection of a synthetic hydrogel with delivery of bFGF and IGF1 in a rat model of ischemic cardiomyopathy. Biomacromolecules 15, 1–11 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Martens, T. P. et al. Percutaneous cell delivery into the heart using hydrogels polymerizing in situ. Cell Transplant. 18, 297–304 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hao, X. et al. Angiogenic effects of sequential release of VEGF-A165 and PDGF-BB with alginate hydrogels after myocardial infarction. Cardiovasc. Res. 75, 178–185 (2007).

    Article  PubMed  CAS  Google Scholar 

  13. Scott, R. C., Crabbe, D., Krynska, B., Ansari, R. & Kiani, M. F. Aiming for the heart: targeted delivery of drugs to diseased cardiac tissue. Expert Opin. Drug Deliv. 5, 459–470 (2008).

    Article  PubMed  CAS  Google Scholar 

  14. Wang, Z. et al. Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart. Nat. Biotechnol. 23, 321–328 (2005).

    Article  PubMed  CAS  Google Scholar 

  15. Mayer, C. R. & Bekeredjian, R. Ultrasonic gene and drug delivery to the cardiovascular system. Adv. Drug Deliv. Rev. 60, 1177–1192 (2008).

    Article  PubMed  CAS  Google Scholar 

  16. Dvir, T. et al. Nanoparticles targeting the infarcted heart. Nano Lett. 11, 4411–4414 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Beeri, R. et al. New efficient catheter-based system for myocardial gene delivery. Circulation 106, 1756–1759 (2002).

    Article  PubMed  CAS  Google Scholar 

  18. Weinbaum, S., Tarbell, J. M. & Damiano, E. R. The structure and function of the endothelial glycocalyx layer. Annu. Rev. Biomed. Eng. 9, 121–167 (2007).

    Article  PubMed  CAS  Google Scholar 

  19. Pelouch, V., Dixon, I. M. C., Golfman, L., Beamish, R. E. & Dhalla, N. S. Role of extracellular matrix proteins in heart function. Mol. Cell. Biochem. 129, 101–120 (1994).

    Article  Google Scholar 

  20. Dai, J. & Mumper, R. J. Plant phenolics: extraction, analysis and their antioxidant and anticancer properties. Molecules 15, 7313–7352 (2010).

    Article  PubMed  CAS  Google Scholar 

  21. Sileika, T. S. et al. Colorless multifunctional coatings inspired by polyphenols found in tea, chocolate, and wine. Angew. Chem. Int. Ed. 52, 10766–10770 (2013).

    Article  CAS  Google Scholar 

  22. Ejima, H. et al. One-step assembly of coordination complexes for versatile film and particle engineering. Science 341, 154–157 (2013).

    Article  PubMed  CAS  Google Scholar 

  23. Shin, M. et al. DNA/tannic acid hybrid gel exhibiting biodegradability, extensibility, tissue adhesiveness, and hemostatic ability. Adv. Funct. Mater. 25, 1270–1278 (2015).

    Article  CAS  Google Scholar 

  24. Khan, N. S., Ahmad, A. & Hadi, S. M. Anti-oxidant, pro-oxidant properties of tannic acid and its binding to DNA. Chem. Biol. Interact. 125, 177–189 (2000).

    Article  PubMed  CAS  Google Scholar 

  25. Shukla, A., Fang, J. C., Puranam, S., Jensen, F. R. & Hammond, P. T. Hemostatic multilayer coatings. Adv. Mater. 24, 492–496 (2012).

    Article  PubMed  CAS  Google Scholar 

  26. Van Buren, J. P. & Robinson, W. B. Formation of complexes between protein and tannic acid. J. Agric. Food Chem. 17, 772–777 (1969).

    Article  CAS  Google Scholar 

  27. Heijmen, F. H., Du Pant, J. S., Middelkoop, E., Kreis, R. W. & Hoekstra, M. J. Cross-linking of dermal sheep collagen with tannic acid. Biomaterials 18, 749–754 (1997).

    Article  PubMed  CAS  Google Scholar 

  28. Shin, M., Kim, K., Shim, W., Yang, J. W. & Lee, H. Tannic acid as a degradable mucoadhesive compound. ACS Biomater. Sci. Eng. 2, 687–696 (2016).

    Article  CAS  Google Scholar 

  29. Ma, S., Lee, H., Liang, Y. & Zhou, F. Astringent mouthfeel as a consequence of lubrication failure. Angew. Chem. Int. Ed. 128, 5887–5891 (2016).

    Article  Google Scholar 

  30. Siebert, K. J., Troukhanova, N. V. & Lynn, P. Y. Nature of polyphenol−protein interactions. J. Agric. Food Chem. 44, 80–85 (1996).

    Article  CAS  Google Scholar 

  31. Bate-Smith, E. C. Haemanalysis of tannins: the concept of relative astringency. Phytochemistry 12, 907–912 (1973).

    Article  CAS  Google Scholar 

  32. Chung, J. E. et al. Self-assembled micellar nanocomplexes comprising green tea catechin derivatives and protein drugs for cancer therapy. Nat. Nanotech. 9, 907–912 (2014).

    Article  CAS  Google Scholar 

  33. Mero, A., Ishino, T., Chaiken, I., Veronese, F. M. & Pasut, G. Multivalent and flexible PEG-nitrilotriacetic acid derivatives for non-covalent protein pegylation. Pharm. Res. 28, 2412–2421 (2011).

    Article  PubMed  CAS  Google Scholar 

  34. Torchilin, V. P. Micellar nanocarriers: pharmaceutical perspectives. Pharm. Res. 24, 1–16 (2007).

    Article  PubMed  CAS  Google Scholar 

  35. Sonavanea, G., Tomoda, K. & Makino, K. Biodistribution of colloidal gold nanoparticles after intravenous administration: effect of particle size. Colloids Surf. B Biointerfaces 66, 274–280 (2008).

    Article  CAS  Google Scholar 

  36. Papadopoulou, A., Green, R. J. & Frazier, R. A. Interaction of flavonoids with bovine serum albumin: a fluorescence quenching study. J. Agric. Food Chem. 53, 158–163 (2005).

    Article  PubMed  CAS  Google Scholar 

  37. Yokoyama, M. et al. Toxicity and antitumor activity against solid tumors of micelle-forming polymeric anticancer drug and its extremely long circulation in blood. Cancer Res. 51, 3229–3236 (1991).

    PubMed  CAS  Google Scholar 

  38. Isenburg, J. C., Simionescu, D. T. & Vyavahare, N. R. Elastin stabilization in cardiovascular implants: improved resistance to enzymatic degradation by treatment with tannic acid. Biomaterials 25, 3293–3302 (2004).

    Article  PubMed  CAS  Google Scholar 

  39. Isenburg, J. C., Simionescu, D. T. & Vyavahare, N. R. Tannic acid treatment enhances biostability and reduces calcification of glutaraldehyde fixed aortic wall. Biomaterials 26, 1237–1245 (2005).

    Article  PubMed  CAS  Google Scholar 

  40. Lu, Y. & Bennick, A. Interaction of tannin with human salivary proline-rich proteins. Arch. Oral Biol. 43, 717–728 (1998).

    Article  PubMed  CAS  Google Scholar 

  41. Weber, L., Kirsch, E., Moller, P. & Krieg, T. Collagen type distribution and macromolecular organization of connective tissue in different layers of human skin. J. Invest. Dermatol. 82, 156–160 (1984).

    Article  PubMed  CAS  Google Scholar 

  42. Green, R. J. et al. Surface plasmon resonance analysis of dynamic biological interactions with biomaterials. Biomaterials 21, 1823–1835 (2000).

    Article  PubMed  CAS  Google Scholar 

  43. Poncet-Legrand, C., Gautier, C., Cheynier, V. & Imberty, A. Interactions between flavan-3-ols and poly(l-proline) studied by isothermal titration calorimetry: effect of the tannin structure. J. Agric. Food Chem. 55, 9235–9240 (2007).

    Article  PubMed  CAS  Google Scholar 

  44. Frazier, R. A., Papadopoulou, A., Mueller-Harvey, I., Kissoon, D. & Green, R. J. Probing protein–tannin interactions by isothermal titration microcalorimetry. J. Agric. Food Chem. 51, 5189–5195 (2003).

    Article  PubMed  CAS  Google Scholar 

  45. Frasca, V. Biophysical characterization of antibodies with isothermal titration calorimetry. J. Appl. Bioanal. 2, 90–102 (2016).

    Article  CAS  Google Scholar 

  46. Hong, H. S. et al. A new role of substance P as an injury-inducible messenger for mobilization of CD29+ stromal-like cells. Nat. Med. 15, 425–435 (2009).

    Article  PubMed  CAS  Google Scholar 

  47. Hearse, D. J. & Bolli, R. Reperfusion induced injury: manifestations, mechanisms, and clinical relevance. Cardiovasc. Res. 26, 101–108 (1992).

    Article  PubMed  CAS  Google Scholar 

  48. Sides, G. D. QT interval prolongation as a biomarker for torsades de pointes and sudden death in drug development. Dis. Markers 18, 57–62 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Hondeghem, L. M., Carlsson, L. & Duker, G. Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic. Circulation 103, 2004–2013 (2001).

    Article  PubMed  CAS  Google Scholar 

  50. Pacher, P., Nagayama, T., Mukhopadhyay, P., Bátkai, S. & Kass, D. A. Measurement of cardiac function using pressure–volume conductance catheter technique in mice and rats. Nat. Protoc. 3, 1422–1434 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Weiss, J. L., Frederiksen, J. W. & Weisfeldt, M. L. Hemodynamic determinants of the time-course of fall in canine left ventricular pressure. J. Clin. Invest. 58, 751–760 (1976).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Zhu, F. et al. New findings on the effects of tannic acid: inhibition of L-type calcium channels, calcium transient and contractility in rat ventricular myocytes. Phytother. Res. 30, 510–516 (2016).

    Article  PubMed  CAS  Google Scholar 

  53. Park, J. H. et al. A cytoprotective and degradable metal–polyphenol nanoshell for single-cell encapsulation. Angew. Chem. Int. Ed. 53, 12420–12425 (2014).

    CAS  Google Scholar 

  54. Awada, H. K. et al. A single injection of protein-loaded coacervate-gel significantly improves cardiac function post infarction. Biomaterials 125, 65–80 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Chu, H., Chen, C.-W., Huard, J. & Wang, Y. The effect of a heparin-based coacervate of fibroblast growth factor-2 on scarring in the infarcted myocardium. Biomaterials 34, 1747–1756 (2013).

    Article  PubMed  CAS  Google Scholar 

  56. Jang, J.-H. et al. An evolved adeno-associated viral variant enhances gene delivery and gene targeting in neural stem cells. Mol. Ther. 19, 667–675 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (1631060 to H.L.). This work was also supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science, ICT and Future Planning for the following convergent research: a development programme for convergence research and development in traditional culture and current technology (NRF-2016M3C1B5906485 to H.L.), the Mid-career Researcher Program (NRF-2017R1A2A1A05001047 to H.L.) and the Basic Science Research Program funded by the Ministry of Education (NRF-2016R1A6A3A11933589 to M.S.). Further support was provided by the Technology Innovation Program (an establishment of risk management platform with the aim of reducing the attrition of new drugs and services) funded by the Ministry of Trade, Industry and Energy (10067737 (K.-S.K.)). The authors also thank B. S. Choi and H. N. Kim for advice on the ITC experiments.

Author information

Author notes

  1. These authors contributed equally: Mikyung Shin and Hyang-Ae Lee.

  2. These authors jointly supervised this work: Ki-Suk Kim and Haeshin Lee.

Authors and Affiliations

  1. Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea

    Mikyung Shin, Mihyun Lee, Minjae Do & Haeshin Lee

  2. Predictive Model Research Center, Korea Institute of Toxicology, Daejeon, Republic of Korea

    Hyang-Ae Lee, Sun-Woong Kang, Dae-Hwan Nam, SunHyun Park & Ki-Suk Kim

  3. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea

    Yoomi Shin & Ji-Joon Song

  4. Department of Human and Environmental Toxicology, University of Science and Technology, Daejeon, Republic of Korea

    Sun-Woong Kang & Ki-Suk Kim

  5. Department of Biotechnology, Yonsei University, Seoul, Republic of Korea

    Eun Je Jeon & Seung-Woo Cho

  6. Department of Chemical and Biomolecular Engineering, Yonsei University, Seoul, Republic of Korea

    Mira Cho & Jae-Hyung Jang

  7. R&D Center, InnoTherapy, Seoul, Republic of Korea

    Moon Sue Lee

Authors
  1. Mikyung Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyang-Ae Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mihyun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoomi Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ji-Joon Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sun-Woong Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dae-Hwan Nam
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eun Je Jeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mira Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Minjae Do
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. SunHyun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Moon Sue Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jae-Hyung Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Seung-Woo Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ki-Suk Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Haeshin Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.S. conceived and designed the experiments. M.S., H.-A.L., M.L., D.-H.N. and S.H.P. performed the in vivo experiments on heart accumulation, cardiotoxicity and therapeutic efficacy for the MIR disease model. Y.S. and J.-J.S. prepared the GFP. E.J.J. performed the in vitro experiments for SP. M.C. prepared the AAV9-encoding GFP. M.D. prepared the AAV2-encoding GFP. M.S., H.-A.L., S.-W.K., S.-W.C., M.S.L., J.-H.J., K.-S.K. and H.L. discussed and interpreted the results. M.S., H.-A.L. K.-S.K and H.L. wrote the paper. M.S., H.L. and K.-S.K. supervised the project.

Corresponding authors

Correspondence to Ki-Suk Kim or Haeshin Lee.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary figures and tables.

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shin, M., Lee, HA., Lee, M. et al. Targeting protein and peptide therapeutics to the heart via tannic acid modification. Nat Biomed Eng 2, 304–317 (2018). https://doi.org/10.1038/s41551-018-0227-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41551-018-0227-9

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research