3 years ago

Dual-Drug Delivery Using Dextran-Functionalized Nanoparticles Targeting Cardiac Fibroblasts for Cellular Reprogramming

Dual-Drug Delivery Using Dextran-Functionalized Nanoparticles Targeting Cardiac Fibroblasts for Cellular Reprogramming
João F. Pinto, Virpi Talman, Mónica P. A. Ferreira, Zehua Liu, Jouni Hirvonen, Dongfei Liu, Hélder A. Santos, Heikki Ruskoaho, Gonçalo Marques, Giulia Torrieri, Karina Moslova
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 β-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. Pharmacological cellular reprogramming is a highly relevant therapeutic strategy toward cardiac regeneration, and the application of nanoparticles in this emerging field is scarcely explored. Here, a dual-loaded multifunctional and cardiac-specific nanoparticulate system for potential application in cellular reprogramming of nonmyocytes into cardiomyocyte-like cells is reported, promoting pH-triggered drug delivery and modulation of signaling factors involved in cardiac reprogramming.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/adfm.201705134

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