Curcumin Nanoparticles Inhibiting Ferroptosis for the Enhanced Treatment of Intracerebral Hemorrhage

Abstract

Background Intracerebral hemorrhage (ICH) is a form of severe stroke, the pathology of which is tied closely to a recently discovered form of programmed cell death known as ferroptosis. Curcumin (Cur) is a common phenolic compound extracted from the rhizome of Curcuma longa capable of hematoma volume and associated neurological damage in the context of ICH. Despite exhibiting therapeutic promise, the efficacy of Cur is challenged by its poor water solubility, limited oral bioavailability and inability to efficiently transit across the physiological barriers. Polymer-based nanoparticles (NPs) have widely been employed to aid in drug delivery efforts owing to their ideal biocompatibility and their ability to improve the bioavailability and pharmacokinetics of specific drugs of interest. Methods In this study, we encapsulated Cur in NPs (Cur-NPs) and explored the effect of these Cur-NPs to enhance Cur delivery both in vitro and in vivo. Furthermore, we evaluated the anti-ferroptosis effect of Cur-NPs in ICH model mice and erastin-treated HT22 murine hippocampal cells. Results The resultant Cur-NPs were spherical and exhibited a particle size of 127.31±2.73 nm, a PDI of 0.21±0.01 and a zeta potential of −0.25±0.02 mV. When applied to Madin Darby canine kidney (MDCK) cells in vitro, these Cur-NPs were nonspecifically internalized via multiple endocytic pathways, with plasma membrane microcapsules and clathrin-mediated uptake being the dominant mechanisms. Within cells, these NPs accumulated in lysosomes, endoplasmic reticulum and mitochondria. Cur-NPs were capable of passing through physiological barriers in a zebrafish model system. When administrated to C57BL/6 mice, they significantly improved Cur delivery to the brain. Most notably, when administered to ICH model mice, Cur-NPs achieved superior therapeutic outcomes relative to other treatments. In a final series of experiments, these Cur-NPs were shown to suppress erastin-induced ferroptosis in HT22 murine hippocampal cells. Conclusion These Cur-NPs represent a promising means of improving Cur delivery to the brain and thereby better treating ICH.

Ferroptosis and Its Role in Chronic Diseases

“…Intracerebral hemorrhage (ICH) is a type of severe stroke, the pathology of which is closely related to ferroptosis. Curcumin nanoparticles inhibit ferroptosis and enhance ICH treatment [129], and baicalin can also suppress ferroptosis in ICH [130]. Tau-mediated iron export inhibits ferroptosis after ischemic stroke [131].…”

“…Curcumin decreases rhabdomyolysis-related renal damage by reducing ferroptosis, and mechanistic studies have shown that curcumin downregulates the TLR4/NF-κB axis and activates HO-1 [220]. Since curcumin nanoparticles suppress ferroptosis, they can be used to strengthen the treatment of ICH [129]. Curcumin also induces the ferroptosis of breast cancer cells by upregulating SLC1A5 [99].…”

Targeting Oxidative Stress Involved in Endometriosis and Its Pain

“…Chen et al, demonstrated that a curcumin analog could induce ferroptosis and suppress GPX4 [ 141 ]. Another study by Yan et al, utilized curcumin nanoparticles and demonstrated an opposing effect of ferroptosis inhibition [ 142 ]. Information on the connection between curcumin and its effects on ferroptosis in endometriosis is still limited and needs further investigation.…”

“…Clinical trials have suggested that 3.6 g of curcumin taken orally for cancer treatment is a therapeutically effective dosage [ 146 ]. Various formulations of curcumin have been produced to address the issues of its pharmacokinetics, poor bioavailability, and low solubility when taken orally [ 142 , 147 ]. Some of these formulations include phospholipid complexes, micelles, liposomes, nanoparticles, and micro-formulations which increase the solubility and improve its cellular uptake [ 147 ].…”

Natural Antioxidant Compounds as Potential Pharmaceutical Tools against Neurodegenerative Diseases

“… 128 One of the most promising approaches involving the use of curcumin is represented by the exploitation of nanostructures composed mostly of curcumin, commonly referred to as “nanocurcumin”. 126 , 131 − 134 Nanocurcumin is commonly obtained through precipitation methods, usually in the presence of stabilizers such as polyethylene glycol (PEG) 126 or polyvinylpyrrolidone (PVP). 131 Nanocurcumin has shown potential for the treatment of neurological diseases not only in animals (such as on in vivo models of MS 132 ) but also even in clinical trials.…”