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Reduction of liver fibrosis by rationally designed macromolecular telmisartan prodrugs

A Publisher Correction to this article was published on 03 September 2018

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At present there are no drugs for the treatment of chronic liver fibrosis that have been approved by the Food and Drug Administration of the United States. Telmisartan, a small-molecule antihypertensive drug, displays antifibrotic activity, but its clinical use is limited because it causes systemic hypotension. Here, we report the scalable and convergent synthesis of macromolecular telmisartan prodrugs optimized for preferential release in diseased liver tissue. We have optimized the release of active telmisartan in fibrotic liver to be depot-like (that is, a constant therapeutic concentration) through the molecular design of telmisartan brush-arm star polymers, and show that these lead to improved efficacy and to the avoidance of dose-limiting hypotension in both metabolically and chemically induced mouse models of hepatic fibrosis, as determined by histopathology, enzyme levels in the liver, intact-tissue protein markers, hepatocyte necrosis protection and gene-expression analyses. In rats and dogs, the prodrugs are retained long term in liver tissue, and have a well-tolerated safety profile. Our findings support the further development of telmisartan prodrugs that enable infrequent dosing in the treatment of liver fibrosis.

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Fig. 1: Rational design of TEL-x-MM and semi-batch synthesis of TEL-x-BASP.
Fig. 2: PK and BD data for TEL-x-BASPs in healthy mice.
Fig. 3: Scalable synthesis of TEL-2-BASP.
Fig. 4: Safety and pharmacokinetic analysis of TEL-2-BASP in rodents.
Fig. 5: Design and efficacy of TEL-2-BASP and TEL in a chemically induced CCl4 mouse model.
Fig. 6: Assessing fibrosis reversal with PSR histological images.

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  • 03 September 2018

    In the version of this Article originally published, the author Peter Blume-Jensen was not denoted as a corresponding author; this has now been amended and the author’s email address has been added. The ‘Correspondence and requests for materials’ statement was similarly affected and has now been updated with the author’s initials ‘P.B-J.’


  1. Mokdad, A. A. et al. Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Medicine 12, 145 (2014).

    Article  Google Scholar 

  2. Friedman, S. L., Sheppard, D., Duffield, J. S. & Violette, S. Therapy for fibrotic diseases: nearing the starting line. Sci. Transl. Med. 5, 167sr161 (2013).

    Article  Google Scholar 

  3. Fleming, K. M., Aithal, G. P., Card, T. R. & West, J. All-cause mortality in people with cirrhosis compared with the general population: a population-based cohort study. Liver Int. 32, 79–84 (2012).

    Article  Google Scholar 

  4. Trautwein, C., Friedman, S. L., Schuppan, D. & Pinzani, M. Hepatic fibrosis: concept to treatment. J. Hepatol. 62 (Suppl. 1), S15–S24 (2015).

    Article  Google Scholar 

  5. Lee, Y. A., Wallace, M. C. & Friedman, S. L. Pathobiology of liver fibrosis: a translational success story. Gut 64, 830 (2015).

    Article  CAS  Google Scholar 

  6. Wynn, T. A. Cellular and molecular mechanisms of fibrosis. J. Pathol. 214, 199–210 (2008).

    Article  CAS  Google Scholar 

  7. Bataller, R. & Brenner, D. A. Liver fibrosis. J. Clin. Investig. 115, 209–218 (2005).

    Article  CAS  Google Scholar 

  8. Georgescu, E. F., Ionescu, R., Niculescu, M., Mogoanta, L. & Vancica, L. Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis. World J. Gastroenterol. 15, 942–954 (2009).

    Article  CAS  Google Scholar 

  9. Micardis (Boehringer-Ingelheim, 2014);

  10. Chauhan, V. P. et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat. Commun. 4, 2516 (2013).

    Article  Google Scholar 

  11. Ge, P. S. & Runyon, B. A. Treatment of patients with cirrhosis. N. Engl. J. Med. 375, 767–777 (2016).

    Article  CAS  Google Scholar 

  12. Hamidreza, N. L. Polymeric conjugates for drug delivery. Chem. Mater. 24, 840–853 (2012).

    Article  Google Scholar 

  13. Kinnear, C., Moore, T. L., Rodriguez-lorenzo, L., Rothen-Rutishauser, B. & Petri-fink, A. Form follows function: nanoparticle shape and its implications for nanomedicine. Chem. Rev. 117, 11476–11521 (2017).

    Article  CAS  Google Scholar 

  14. Blanco, E., Shen, H. & Ferrari, M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33, 941–951 (2015).

    Article  CAS  Google Scholar 

  15. Giannitrapani, L., Soresi, M., Bondì, M. L., Montalto, G. & Cervello, M. Nanotechnology applications for the therapy of liver fibrosis. World J. Gastroenterol. 20, 7242–7251 (2014).

    Article  Google Scholar 

  16. Conner, S. D. & Schmid, S. L. Regulated portals of entry into the cell. Nature 422, 37–44 (2003).

    Article  CAS  Google Scholar 

  17. Bartneck, M., Warzecha, K. T. & Tacke, F. Therapeutic targeting of liver inflammation and fibrosis by nanomedicine. Hepatobiliary Surg. Nutr. 3, 364–376 (2014).

    PubMed  PubMed Central  Google Scholar 

  18. Ahmad, Z., Shah, A., Siddiq, M. & Kraatz, H. B. Polymeric micelles as drug delivery vehicles. RSC Adv. 4, 17028–17028 (2014).

    Article  CAS  Google Scholar 

  19. Leroux, J.-C. Too much complexity, not enough reproducibility? Angew. Chem. Int. Ed. 56, 15170–15171 (2017).

    Article  CAS  Google Scholar 

  20. Bobo, D., Robinson, K. J., Islam, J., Thurecht, K. J. & Corrie, S. R. Nanoparticle-based medicines: a review of FDA-approved materials and clinical trials to date. Pharm. Res. 33, 2373–2387 (2016).

    Article  CAS  Google Scholar 

  21. Johnson, J. A. et al. Drug-loaded, bivalent-bottle-brush polymers by graft-through ROMP. Macromolecules 43, 10326–10335 (2010).

    Article  CAS  Google Scholar 

  22. Johnson, J. A. et al. Core-clickable PEG-branch-azide bivalent-bottle-brush polymers by ROMP: grafting-through and clicking-to. J. Am. Chem. Soc. 133, 559–566 (2011).

    Article  CAS  Google Scholar 

  23. Liu, J. et al. ‘Brush-first’ method for the parallel synthesis of photocleavable, nitroxide-labeled poly(ethylene glycol) star polymers. J. Am. Chem. Soc. 134, 16337–16344 (2012).

    Article  CAS  Google Scholar 

  24. Liao, L. et al. A convergent synthetic platform for single-nanoparticle combination cancer therapy: ratiometric loading and controlled release of cisplatin, doxorubicin, and camptothecin. J. Am. Chem. Soc. 136, 5896–5899 (2014).

    Article  CAS  Google Scholar 

  25. Gao, A. X., Liao, L. & Johnson, J. A. Synthesis of acid-labile PEG and PEG–doxorubicin-conjugate nanoparticles via brush-first ROMP. ACS Macro Lett. 3, 854–857 (2014).

    Article  CAS  Google Scholar 

  26. Barnes, J. C. et al. Using an RNAi signature assay to guide the design of three-drug-conjugated nanoparticles with validated mechanisms, in vivo efficacy, and low toxicity. J. Am. Chem. Soc. 138, 12494–12501 (2016).

    Article  CAS  Google Scholar 

  27. Liederer, B. M. & Borchardt, R. T. Enzymes involved in the bioconversion of ester-based prodrugs. J. Pharm. Sci. 95, 1177–1195 (2006).

    Article  CAS  Google Scholar 

  28. Cabral, H. et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat. Nanotech. 6, 815–823 (2011).

    Article  CAS  Google Scholar 

  29. Jain, R. K. Antiangiogenesis strategies revisited: Ffrom starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014).

    Article  CAS  Google Scholar 

  30. Baumann, A., Tuerck, D., Prabhu, S., Dickmann, L. & Sims, J. Pharmacokinetics, metabolism and distribution of PEGs and PEGylated proteins: quo vadis?. Drug Discov. Today 19, 1623–1631 (2014).

    Article  CAS  Google Scholar 

  31. Ivens, I. A. et al. PEGylated biopharmaceuticals. Toxicol. Pathol. 43, 959–983 (2015).

    Article  CAS  Google Scholar 

  32. M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (FDA, 2010);

  33. Fujii, M. et al. A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma. Med. Mol. Morphol. 46, 141–152 (2013).

    Article  CAS  Google Scholar 

  34. Takaura, K. et al. Characterization of non-alcoholic steatohepatitis-derived hepatocellular carcinoma as a human stratification model in mice. Anticancer Res. 34, 4849–4855 (2014).

    Google Scholar 

  35. Nair, A. B. & Jacob, S. A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm. 7, 27–31 (2016).

    Article  Google Scholar 

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Funding was provided by XTuit Pharmaceuticals. J.A.J. acknowledges the National Institutes of Health (1R01CA220468-01) for support of this work. M.R.G. acknowledges the National Institutes of Health for a postdoctoral fellowship (1F32EB023101). H.V.-T.N. thanks the National Science Foundation for a Graduate Research Fellowship. The authors thank R. Bronson for assistance with histopathology analysis.

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Authors and Affiliations



M.R.G., J.L. and J.A.J. designed synthetic experiments. M.R.G., J.L., F.V., H.V.-T.N. and D.C.E. synthesized materials. J.L., J.K.S.-S., P.W.K. and D.E.C. developed the scaled process and produced materials for the safety and toxicology studies. J.N.A. and P.B.-J. planned in vivo experiments. P.B-J. and M.V.S. planned biomarker analyses. M.V.S., S.J.H., B.V., A.M.N., J.C.A. and J.B. performed biomarker analyses. All authors helped to analyse data. M.R.G., J.N.A., P.B.-J. and J.A.J wrote the manuscript. All authors read and edited the manuscript.

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Correspondence to Peter Blume-Jensen or Jeremiah A. Johnson.

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Competing interests

J.L., J.N.A., M.V.S., S.J.H., B.V., K.D.E., A.M.N., J.C.A., J.B., S.P., S.W.B., E.J.H., J.K.S.-S., P.W.K., D.E.C. and P.B.-J. are former employees and shareholders of XTuit Pharmaceuticals. P.B.-J. is President and Founder of Acrivon Therapeutics. J.A.J. is a Co-Founder of Acrivon Therapeutics.

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Golder, M.R., Liu, J., Andersen, J.N. et al. Reduction of liver fibrosis by rationally designed macromolecular telmisartan prodrugs. Nat Biomed Eng 2, 822–830 (2018).

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