Charge effect of a liposomal delivery system encapsulating simvastatin to treat experimental ischemic stroke in rats

Abstract

Background and aims Although the beneficial effects of statins on stroke have been widely demonstrated both in experimental studies and in clinical trials, the aim of this study is to prepare and characterize a new liposomal delivery system that encapsulates simvastatin to improve its delivery into the brain. Materials and methods In order to select the optimal liposome lipid composition with the highest capacity to reach the brain, male Wistar rats were submitted to sham or transitory middle cerebral arterial occlusion (MCAOt) surgery and treated (intravenous [IV]) with fluorescent-labeled liposomes with different net surface charges. Ninety minutes after the administration of liposomes, the brain, blood, liver, lungs, spleen, and kidneys were evaluated ex vivo using the Xenogen IVIS ® Spectrum imaging system to detect the load of fluorescent liposomes. In a second substudy, simvastatin was assessed upon reaching the brain, comparing free and encapsulated simvastatin (IV) administration. For this purpose, simvastatin levels in brain homogenates from sham or MCAOt rats at 2 hours or 4 hours after receiving the treatment were detected through ultra-high-protein liquid chromatography. Results Whereas positively charged liposomes were not detected in brain or plasma 90 minutes after their administration, neutral and negatively charged liposomes were able to reach the brain and accumulate specifically in the infarcted area. Moreover, neutral liposomes exhibited higher bioavailability in plasma 4 hours after being administered. The detection of simvastatin by ultra-high-protein liquid chromatography confirmed its ability to cross the blood–brain barrier, when administered either as a free drug or encapsulated into liposomes. Conclusion This study confirms that liposome charge is critical to promote its accumulation in the brain infarct after MCAOt. Furthermore, simvastatin can be delivered after being encapsulated. Thus, simvastatin encapsulation might be a promising strategy to ensure that the drug reaches the brain, while increasing its bioavailability and reducing possible side effects.

Acute and subacute toxicity profiles of thymoquinone-loaded nanostructured lipid carrier in BALB/c mice

“…These nanoparticle properties can influence the distribution of nanoparticles within the body. 31 The particle size and zeta potential are the main factors affecting the nanoparticle cellular uptake, as observed for other nanoparticles such as polymeric and inorganic particles. 28 The small size of the particles makes nanotechnology very useful in medicine, but it may cause adverse effects in humans.…”

<p>Pharmacokinetics and Biodistribution of Thymoquinone-loaded Nanostructured Lipid Carrier After Oral and Intravenous Administration into Rats</p>

“…21,22,52 The distribution of the nanoparticles within the body is mainly influenced by these characteristics. 53 The release profile of TQ-NLC showed that the concentration of TQ released by NLC was not equivalent to the concentration of TQ alone even after 72 h. Hence, in contrast to pure TQ solution (which showed the burst release profile), the absence of concentration spike was anticipated when the cells were treated with TQ-NLC. 54 lymphatic systems.…”

Recent Advances in the Therapeutic and Diagnostic Use of Liposomes and Carbon Nanomaterials in Ischemic Stroke

“…It is crucial that liposomes can cross the BBB and it is also desirable that they remain in the bloodstream for a long period of time, so as to deliver a sufficient quantity of drug to the brain tissue ( Moghimi et al, 2001 ). The circulation time of liposomes can be enhanced through reduction of particle size or modification of their surface by polyethylene glycol (PEG) ( Fukuta et al, 2014 ; Bozzuto and Molinari, 2015 ; Wang et al, 2015 ; Campos-Martorell et al, 2016 ; Chen and Gao, 2017 ). It has been reported that PEGylated liposomes can accumulate into ischemic brain regions after a stroke event ( Fukuta et al, 2016 ), presumably because of the disruption of the BBB and the enhanced vesicle permeation and retention at the ischemic site.…”

“…The surface charge is another factor that can influence the accumulation of liposomes into the brain. Campos-Martorell et al (2016) showed that neutral and negatively charged PEGylated liposomes administered intravenously were captured to a lower extent by the liver and lungs in comparison to cationic vesicles. As consequence, the neutral and anionic liposomes showed prolonged circulation time in the blood and higher uptake in the ischemic region ( Campos-Martorell et al, 2016 ).…”

“… Campos-Martorell et al (2016) showed that neutral and negatively charged PEGylated liposomes administered intravenously were captured to a lower extent by the liver and lungs in comparison to cationic vesicles. As consequence, the neutral and anionic liposomes showed prolonged circulation time in the blood and higher uptake in the ischemic region ( Campos-Martorell et al, 2016 ). In another study, non-PEGylated liposomes with different surface charges were given through intracarotid injection as an attempt to achieve early brain deposition.…”