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.
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Mokdad, A. A. et al. Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Medicine 12, 145 (2014).
Friedman, S. L., Sheppard, D., Duffield, J. S. & Violette, S. Therapy for fibrotic diseases: nearing the starting line. Sci. Transl. Med. 5, 167sr161 (2013).
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).
Trautwein, C., Friedman, S. L., Schuppan, D. & Pinzani, M. Hepatic fibrosis: concept to treatment. J. Hepatol. 62 (Suppl. 1), S15–S24 (2015).
Lee, Y. A., Wallace, M. C. & Friedman, S. L. Pathobiology of liver fibrosis: a translational success story. Gut 64, 830 (2015).
Wynn, T. A. Cellular and molecular mechanisms of fibrosis. J. Pathol. 214, 199–210 (2008).
Bataller, R. & Brenner, D. A. Liver fibrosis. J. Clin. Investig. 115, 209–218 (2005).
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).
Micardis (Boehringer-Ingelheim, 2014); https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Micardis%20Tabs/MICARDIS20-40-80mg.PDF
Chauhan, V. P. et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat. Commun. 4, 2516 (2013).
Ge, P. S. & Runyon, B. A. Treatment of patients with cirrhosis. N. Engl. J. Med. 375, 767–777 (2016).
Hamidreza, N. L. Polymeric conjugates for drug delivery. Chem. Mater. 24, 840–853 (2012).
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).
Blanco, E., Shen, H. & Ferrari, M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33, 941–951 (2015).
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).
Conner, S. D. & Schmid, S. L. Regulated portals of entry into the cell. Nature 422, 37–44 (2003).
Bartneck, M., Warzecha, K. T. & Tacke, F. Therapeutic targeting of liver inflammation and fibrosis by nanomedicine. Hepatobiliary Surg. Nutr. 3, 364–376 (2014).
Ahmad, Z., Shah, A., Siddiq, M. & Kraatz, H. B. Polymeric micelles as drug delivery vehicles. RSC Adv. 4, 17028–17028 (2014).
Leroux, J.-C. Too much complexity, not enough reproducibility? Angew. Chem. Int. Ed. 56, 15170–15171 (2017).
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).
Johnson, J. A. et al. Drug-loaded, bivalent-bottle-brush polymers by graft-through ROMP. Macromolecules 43, 10326–10335 (2010).
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).
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).
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).
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).
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).
Liederer, B. M. & Borchardt, R. T. Enzymes involved in the bioconversion of ester-based prodrugs. J. Pharm. Sci. 95, 1177–1195 (2006).
Cabral, H. et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat. Nanotech. 6, 815–823 (2011).
Jain, R. K. Antiangiogenesis strategies revisited: Ffrom starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014).
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).
Ivens, I. A. et al. PEGylated biopharmaceuticals. Toxicol. Pathol. 43, 959–983 (2015).
M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (FDA, 2010); http://www.fda.gov/downloads/drugs/guidances/ucm073246.pdf
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).
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).
Nair, A. B. & Jacob, S. A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm. 7, 27–31 (2016).
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.
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.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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). https://doi.org/10.1038/s41551-018-0279-x
Diblock brush-arm star copolymers via a core-first/graft-from approach using γ-cyclodextrin and ROMP: a modular platform for drug delivery
Polymer Chemistry (2020)
Nature Reviews Clinical Oncology (2020)
Advanced Drug Delivery Reviews (2020)
Parallel evolution of polymer chemistry and immunology: Integrating mechanistic biology with materials design
Advanced Drug Delivery Reviews (2020)
ABC triblock bottlebrush copolymer-based injectable hydrogels: design, synthesis, and application to expanding the therapeutic index of cancer immunochemotherapy
Chemical Science (2020)