Journal
ADVANCED FUNCTIONAL MATERIALS
Volume 28, Issue 15, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adfm.201705134
Keywords
atrial natriuretic peptides; heart; nanoparticles; small drug molecules; targeted drug delivery
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Funding
- Drug Research Doctoral Programme of the University of Helsinki
- Academy of Finland [266661]
- Sigrid Juselius Foundation
- Tekes large strategic research opening 3i Regeneration [40395/13]
- University of Helsinki Research Funds
- Sigrid Juselius Foundation [4704580]
- European Research Council under the European Union's Seventh Framework Programme [310892]
- Biocenter Finland: Electron Microscopy Unit of the University of Helsinki
- Light Microscopy Unit of the Institute of Biotechnology
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The inability of the heart to recover from an ischemic insult leads to the formation of fibrotic scar tissue and heart failure. From the therapeutic strategies under investigation, cardiac regeneration holds the promise of restoring the full functionality of a damaged heart. Taking into consideration the presence of vast numbers of fibroblasts and myofibroblasts in the injured heart, direct fibroblast reprogramming into cardiomyocytes using small drug molecules is an attractive therapeutic option to replenish the lost cardiomyocytes. Here, a spermine-acetalated dextran-based functional nanoparticle is developed for pH-triggered drug delivery of two poorly water soluble small molecules, CHIR99021 and SB431542, both capable of increasing the efficiency of direct reprogramming of fibroblast into cardiomyocytes. Upon functionalization with polyethylene glycol and atrial natriuretic peptide, the biocompatibility of the nanosystem is improved, and the cellular interactions with the cardiac nonmyocytes are specifically augmented. The dual delivery of the compounds is verified in vitro, and the compounds exerted concomitantly anticipate biological effects by stabilizing beta-catenin (CHIR99021) and by preventing translocation of Smad3 to the nucleus of (myo)fibroblasts (SB431542). These observations highlight the potential of this nanoparticle-based system toward improved drug delivery and efficient direct reprogramming of fibroblasts into cardiomyocyte-like cells, and thus, potential cardiac regeneration therapy.
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