Abstract
Diabetic nephropathy (DN) ranks among the most detrimental long-term effects of diabetes, affecting more than 30% of all patients. Within the diseased kidney, intraglomerular mesangial cells play a key role in facilitating the pro-fibrotic turnover of extracellular matrix components and a progredient glomerular hyperproliferation. These pathological effects are in part caused by an impaired functionality of soluble guanylate cyclase (sGC) and a consequentially reduced synthesis of anti-fibrotic messenger 3′,5′-cyclic guanosine monophosphate (cGMP). Bay 58-2667 (cinaciguat) is able to re-activate defective sGC; however, the drug suffers from poor bioavailability and its systemic administration is linked to adverse events such as severe hypotension, which can hamper the therapeutic effect. In this study, cinaciguat was therefore efficiently encapsulated into virus-mimetic nanoparticles (NPs) that are able to specifically target renal mesangial cells and therefore increase the intracellular drug accumulation. NP-assisted drug delivery thereby increased in vitro potency of cinaciguat-induced sGC stabilization and activation, as well as the related downstream signaling 4- to 5-fold. Additionally, administration of drug-loaded NPs provided a considerable suppression of the non-canonical transforming growth factor β (TGF-β) signaling pathway and the resulting pro-fibrotic remodeling by 50–100%, making the system a promising tool for a more refined therapy of DN and other related kidney pathologies.
Highlights
With an estimated number of almost 500 million cases worldwide and an ever-growing prevalence throughout all age groups, diabetes ranks among the top global causes of death [1]
Initial research on CCG was mainly focused on its therapeutic effects regarding the cardiovascular system [26]; there is promising evidence concerning a beneficial role in the above-discussed renal fibrosis and hyperproliferation [27,28,29], whereby a CCG-mediated soluble form of the guanylate cyclase (sGC) activation has been shown to reduce transforming growth factor β (TGF-β) expression as well as non-canonical TGF-β signaling via extracellular-regulated protein kinase 1/2 (ERK 1/2) [30,31]
The NP itself thereby consisted of shell-forming poly(ethylene glycol)−poly(lactic acid) (PEG-PLA) block-copolymers carrying the above-described targeting functionalities, as well as poly(lactic-co-glycolic acid) (PLGA), which both stabilizes the NP core and can be used to encapsulate suitable active agents such as CCG (Figure 1b)
Summary
With an estimated number of almost 500 million cases worldwide and an ever-growing prevalence throughout all age groups, diabetes ranks among the top global causes of death [1]. Initial research on CCG was mainly focused on its therapeutic effects regarding the cardiovascular system [26]; there is promising evidence concerning a beneficial role in the above-discussed renal fibrosis and hyperproliferation [27,28,29], whereby a CCG-mediated sGC activation has been shown to reduce TGF-β expression as well as non-canonical TGF-β signaling via extracellular-regulated protein kinase 1/2 (ERK 1/2) [30,31] While these results were highly encouraging, CCG can potentially cause unfavorable adverse events, such as a strong hypotension, due to its imminent effect on the vasculature after a systemic administration [32]. CCG would substantially profit from a drug delivery system that is able to considerably increase the drug accumulation in target regions, such as the above-discussed mesangium, while minimizing interactions with off-target sites, such as the vasculature
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