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

Abstract

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.

Dual-peptide functionalized acetalated dextran-based nanoparticles for sequential targeting of macrophages during myocardial infarction

“…[47][48][49] Even though the drug release was faster at pH 5.0, there was a small amount of drugs released already at pH 7.4, which is justifiable by a slight degradation of AcDEX at this pH, as previously reported. 5,50 This loss of drugs at pH 7.4 can also justify the decrease of the LD and EE values of the nanoparticles after the various conjugation steps. After PEGylation, washings were performed in a solution of 2% of sucrose at pH 7.4, in order to prevent the degradation of the maleimide groups of PEG needed to interact with the thiol groups of the TT1 peptide.…”

“…The advent of nanomedicine has brought new insights in innovative treatment strategies, currently at the pre-clinical stage, of CVD, in particular MI. [5][6][7][8][9][10] Such approaches are very promising, but there is urgent need for smart targeting strategies. The infarcted tissue is challenging to address due to mechanical obstacles, like the constant pumping of the organ and the restless massive exchange of blood.…”

“…26,27 The polymer was modified with putrescine to provide functional groups for further surface conjugations and to reduce the toxicity towards primary cardiomyocytes observed with spermine-modified nanoparticles. 5 Spermine particles are highly positively charged even after the conjugations, due to free amine groups present in the structure. The system was loaded with two small hydrophobic compounds, CHIR99021 and SB203580, which have shown a synergistic effect in stimulating cardiomyocyte proliferation.…”

Combining Nanomaterials and Developmental Pathways to Design New Treatments for Cardiac Regeneration: The Pulsing Heart of Advanced Therapies

“…In the context of cell reprogramming, spermine-modified acetylated dextran (AcDXSp) nanoparticles have been designed to encapsulate poorly water-soluble drugs (SB431542transforming growth factor β (TGFβ) inhibitor -and CHIR99021 -Glycogen synthase kinase-3 (GSK3) inhibitor) used to reprogram fibroblasts (Ferreira et al, 2018). These NPs were also tagged with a targeting peptide (atrial natriuretic peptide, ANP) specific for cardiac fibroblasts.…”

Fabrication of Carboxylmethyl Chitosan Nanocarrier via Self-Assembly for Efficient Delivery of Phenylethyl Resorcinol in B16 Cells

“…Due to their biosafety and biodegradable character, self-assembled nanoparticles such as lipid, polylactic-co-glycolic acid (PLGA), polyamidoamine (PAMAM) dendrimers and polysaccharide based nanoparticles consisting of an internal hydrophobic core and an externally surrounded hydrophilic group, have been widely reported to increase the delivery efficiency and bioavailability of drugs [20][21][22][23]. Among these nanoparticles prepared from polymers, there has been rising interest in nanoscale self-aggregates of natural polysaccharides such as pullulan [24], curdlan [25], dextran [26], alginic acid [27], and chitosan [28]. Carboxymethyl chitosan (CMCS) is one of the water-soluble derivatives of chitosan, which has attracted the most attention and exploration in the field of biomedicine [29].…”