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

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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.

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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 PV loop analysis.
Fig. 7: Therapeutic effects of TANNylated bFGF in MIR models.

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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

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.

Correspondence to Ki-Suk Kim or Haeshin Lee.

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