Novel piperine-loaded Tween-integrated monoolein cubosomes as brain-targeted oral nanomedicine in Alzheimer’s disease: pharmaceutical, biological, and toxicological studies

Abstract

Alzheimer’s disease (AD) is one of the most patient devastating central nervous system diseases with no curative therapy. An effective oral therapy with brain-targeting potential is required that is hampered by blood–brain barrier. Piperine (PIP) is a natural alkaloid with memory enhancing potentials. Oral PIP delivery suffers from its hydrophobicity and first-pass metabolism. In this study, novel Tween-modified monoolein cubosomes (T-cubs) were elaborated as bioactive nanocarriers for brain-targeted oral delivery of PIP. Seven liquid crystalline nanoparticles (cubosomes) were prepared testing different bioactive surfactants (Tween 80, poloxamer, and Cremophor). Full in vitro characterization was carried out based on particle size, zeta potential, polydispersity index, entrapment efficiency, and in vitro release. Morphological examination and structure elucidation were performed using transmission and polarizing microscopes. Sporadic dementia of Alzheimer’s type was induced in 42 male Wistar rats on which full behavioral and biochemical testing was conducted. Brain toxicity was assessed based on Caspase-3 assay for apoptosis and tumor necrosis factor-α for inflammation. Liver and kidney toxicity studies were conducted as well. Among others, T-cubs exhibited optimum particle size (167.00±10.49 nm), polydispersity index (0.18±0.01), and zeta potential (−34.60±0.47 mv) with high entrapment efficiency (86.67%±0.62%). Cubs could significantly sustain PIP in vitro release. In vivo studies revealed T-cubs potential to significantly enhance PIP cognitive effect and even restore cognitive function to the normal level. Superiority of T-cubs over others suggested brain-targeting effect of Tween. Toxicological studies contended safety of cubs on kidney, liver, and even brain. T-cubs exhibited potential anti-inflammatory and anti-apoptotic activity of loaded PIP, indicating potential to stop AD progression that was first suggested in this article. Novel oral nanoparticles elaborated possess promising in vitro and in vivo characteristics with high safety for effective chronic treatment of AD.

Cubosomes: The Next Generation of Smart Lipid Nanoparticles?

“…There are three key mechanisms for loading cubosome samples: within the lipid membrane, tethered to the lipid membrane or localized within the water channels of the cubic phase (see Figure 1). Cubosomes can be loaded either pre-dispersion by colyophilizing the drug molecules with the lipid film [32,67] or adding the cargo to molten lipid, [104] or post-dispersion by loading the cubosomes after formation via incubation. [69,70] To date the majority of reports of loaded cubosomes are of proteins or small molecules incorporated within the lipid membrane and predominantly use single or binary lipid compositions based on monoolein or phytantriol.…”

PEG-<em>b</em>-(PELG-<em>g</em>-PLL) nanoparticles as TNF-&alpha; nanocarriers: potential cerebral ischemia/reperfusion injury therapeutic applications

“…23,33,37,38 TNF-α acts as an effector molecule in brain development and is often involved in different signaling pathways to elicit the activation of macrophages and glial cells for neurotoxin production and to initiate the apoptosis/ death process in neurons. [39][40][41] Until now, the overall role of α α α α α α α α α α α α Figure 5 The levels of sOD, MDa, Il-4, Il-6, Il-8, Il-10, and NO in the rat brain tissue (n=10). Notes: (A) sOD; (B) MDa; (C) Il-4; (D) Il-6; (E) Il-8 and Il-10; (F) NO.…”

<p>Novel Drug Delivery Systems for Loading of Natural Plant Extracts and Their Biomedical Applications</p>

“…224 More examples of herbal loaded cubosome are shown in Table 1. [225][226][227][228][229] Biopolymer-Based Nanocarrier (BBN) They have derived from proteins (such as gelatin, albumin, and milk proteins), polysaccharides (such as chitosan, hyaluronan, dextran, cyclodextrins, pectin, guar gum, cellulose, sodium alginate, and starch), and/or their modified versions, derivatives or their combinations. The most interesting features of these materials that render them to be used for BBN production are a biological realization, bioactivity, biodegradability, less toxicity, easy modification, and simplicity of producing gels from them.…”