Development of coated liposomes loaded with ghrelin for nose-to-brain delivery for the treatment of cachexia

Abstract

The aim of the present study was to develop a ghrelin-containing formulation based on liposomes coated with chitosan intended for nose–brain delivery for the treatment of cachexia. Among the three types of liposomes developed, anionic liposomes provided the best results in terms of encapsulation efficiency (56%) and enzymatic protection against trypsin (20.6% vs 0% for ghrelin alone) and carboxylesterase (81.6% vs 17.2% for ghrelin alone). Ghrelin presented both electrostatic and hydrophobic interactions with the anionic lipid bilayer, as demonstrated by isothermal titration calorimetry. Then, anionic liposomes were coated with N -(2-hydroxy) propyl-3-trimethyl ammonium chitosan chloride. The coating involved a size increment from 146.9±2.7 to 194±6.1 nm, for uncoated and coated liposomes, respectively. The ζ-potential was similarly increased from -0.3±1.2 mV to 6±0.4 mV before and after coating, respectively. Chitosan provided mucoadhesion, with an increase in mucin adsorption of 22.9%. Enhancement of permeation through the Calu3 epithelial monolayer was also observed with 10.8% of ghrelin recovered in the basal compartment in comparison to 0% for ghrelin alone. Finally, aerosols generated from two nasal devices (VP3 and SP270) intended for aqueous dispersion were characterized with either coated or uncoated liposomes. Contrarily to the SP270 device, VP3 device showed minor changes between coated and uncoated liposome aerosols, as shown by their median volume diameters of 38.4±5.76 and 37.6±5.74 µm, respectively. Overall, the results obtained in this study show that the developed formulation delivered by the VP3 device can be considered as a potential candidate for nose–brain delivery of ghrelin.

Chitosan-Based Nanocarriers for Nose to Brain Delivery

“…The coating of anionic liposomes with chitosan resulted in a significant increase in Z-average with a resultant charge of positive (6 mV). The electrostatic interactions of the formulation with the negative sialic acid of mucins increased the mucoadhesion and extended the residence of the formulation in the nasal cavity, and hence enhanced the brain uptake [116]. In a similar report by Salade et al, chitosan-coated anionic liposomes were prepared as liquid and powder formulations for nose-to-brain delivery of ghrelin.…”

“…Salade et al developed ghrelin-containing liposomes formulation coated with chitosan for administration via nasal route for the treatment of cachexia [116]. Ghrelin is an orexigenic peptide hormone.…”

<p>Recent expansions of novel strategies towards the drug targeting into the brain</p>

“…with an aqueous core. [41][42][43] The basic properties of the liposomes like fluidity, rigidity, size and surface behavior may vary with the selection of lipid component and method of preparation. It was first discovered by a British scientist Alec Bangham in 1961.…”

How to characterize a nasal product. The state of the art of in vitro and ex vivo specific methods

“…Moreover, when formulations are dispersed systems (e.g. micro-or nano-suspensions or emulsions), size and charge evaluations are usually performed by laser diffraction or dynamic light scattering and electrophoretic mobility, respectively (Salade et al, 2017). Transmission electron microscopy is another qualitative tool, which provides information about the size, shape and surface aspect of colloids (Pathak and Thassu, 2009).…”

“…polyethylene terephthalate or PTFE coated with collagen (Zhang et al, 2016) and polyester (Seki et al, 2007), with a seeding density of 4-5 × 10 5 cells/cm 2 Grainger et al, 2006). An example of Calu-3 application is their wide use to study the reversible opening of tight junctions caused by chitosans, an excipient used very commonly in the intranasal field (Salade et al, 2017;Ye et al, 2013;Scherließ and Trows, 2011).…”