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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., National Institutes of Health (U.S.) (Grant 1R01CA220468-01), National Institutes of Health (U.S.) (Fellowship 1F32EB023101)

Tissue engineering strategies for cartilage defect repair require technology for local targeted delivery of chondrogenic and anti-inflammatory factors. The objective of this study was to determine the release kinetics of transforming growth factor β1 (TGF-β1) from self-assembling peptide hydrogels, a candidate scaffold for cell transplant therapies, and stimulate chondrogenesis of encapsulated young equine bone marrow stromal cells (BMSCs). Although both peptide and agarose hydrogels retained TGF-β1, fivefold higher retention was found in peptide. Excess unlabeled TGF-β1 minimally displaced retained radiolabeled TGF-β1, demonstrating biologically relevant loading capacity for peptide hydrogels. The initial release from acellular peptide hydrogels was nearly threefold lower than agarose hydrogels, at 18% of loaded TGF-β1 through 3 days as compared to 48% for agarose. At day 21, cumulative release of TGF-β1 was 32–44% from acellular peptide hydrogels, but was 62% from peptide hydrogels with encapsulated BMSCs, likely due to cell-mediated TGF-β1 degradation and release of small labeled species. TGF-β1 loaded peptide hydrogels stimulated chondrogenesis of young equine BMSCs, a relevant preclinical model for treating injuries in young human cohorts. Self-assembling peptide hydrogels can be used to deliver chondrogenic factors to encapsulated cells making them a promising technology for in vivo, cell-based regenerative medicine., National Institutes of Health (U.S.) (NIH EB003805), National Institutes of Health (U.S.) (NIH AR60331), National Institutes of Health (U.S.). Molecular, Cell, and Tissue Biomechanics (Training Grant Fellowship), Arthritis Foundation (postdoctoral fellowship)

Self-assembling peptide hydrogels were modified to deliver transforming growth factor b1 [beta 1](TGF-b1)[TGF beta 1] to encapsulated bone-marrow-derived stromal cells (BMSCs) for cartilage tissue engineering applications using two different approaches: (i) biotin-streptavidin tethering; (ii) adsorption to the peptide scaffold. Initial studies to determine the duration of TGF-b1 [TGF beta 1] medium supplementation necessary to stimulate chondrogenesis showed that 4 days of transient soluble TGF-b1 [TGF beta 1] to newborn bovine BMSCs resulted in 10-fold higher proteoglycan accumulation than TGF-b1-free [TGF beta 1 free]culture after 3 weeks. Subsequently, BMSC-seeded peptide hydrogels with either tethered TGF-b1 [TGF beta 1] (Teth-TGF) or adsorbed TGF-b1 [TGF beta 1] (Ads-TGF) were cultured in the TGF-b1-free [TGF beta 1 free] medium, and chondrogenesis was compared to that for BMSCs encapsulated in unmodified peptide hydrogels, both with and without soluble TGF-b1 [TGF beta 1] medium supplementation. Ads-TGF peptide hydrogels stimulated chondrogenesis of BMSCs as demonstrated by cell proliferation and cartilage-like extracellular matrix accumulation, whereas Teth- TGF did not stimulate chondrogenesis. In parallel experiments, TGF-b1 [TGF beta 1] adsorbed to agarose hydrogels stimulated comparable chondrogenesis. Full-length aggrecan was produced by BMSCs in response to Ads-TGF in both peptide and agarose hydrogels, whereas medium-delivered TGF-b1 [TGF beta 1] stimulated catabolic aggrecan cleavage product formation in agarose but not peptide scaffolds. Smad2/3 was transiently phosphorylated in response to Ads-TGF but not Teth-TGF, whereas medium-delivered TGF-b1 [TGF beta 1] produced sustained signaling, suggesting that dose and signal duration are potentially important for minimizing aggrecan cleavage product formation. Robustness of this technology for use in multiple species and ages was demonstrated by effective chondrogenic stimulation of adult equine BMSCs, a, National Institutes of Health (U.S.) ( (NIH EB003805) (NIH AR33236) (NIH AR45779), National Institutes of Health (U.S.). Molecular, Cell, and Tissue Biomechanics Training Grant Fellowship, Arthritis Foundation