Enhanced Cellular Uptake and Biodistribution of a Synthetic Cannabinoid Loaded in Surface-Modified Poly(lactic-co-glycolic acid) Nanoparticles

Abstract

This article aimed to produce, characterize and evaluate different surface-modified naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (CB13) loaded poly(lactic-co-glycolic acid) nanoparticles in order to improve their oral absorption and in vivo biodistribution. Plain and surface-modified PLGA nanoparticles were successfully prepared using a nanoprecipitation method. Chitosan, Eudragit RS, lecithin and vitamin E were used as surface modifying agents. The NPs were evaluated in terms of mean diameter and size distribution, zeta potential, morphology, drug loading, drug release profiles, mucoadhesive properties, in vitro cell viability and uptake and in vivo biodistribution. Mean particle size distributions in the range of 253-344 nm, spherical shape and controlled zeta potential values were observed depending on the additive employed. High values of entrapment efficiency were obtained for all the formulations. Lecithin and vitamin E modified particles showed higher release rates when compared to the rest of formulations. A clear improvement in ex vivo mucoadhesion properties was observed in the case of chitosan- and Eudragit RS-modified nanoparticles. Chitosan-poly(lactic-co-glycolic acid) nanoparticles showed the highest uptake values on Caco-2 cells. Biodistribution assays proved that most of the particles were accumulated in liver and spleen. An important goal has been achieved in this investigation: CB13, a highly lipophilic drug with low water solubility, can reach the interior of cells more efficiently when it is included in these surface-modified polymeric carriers.

Effect of surface chemistry on nanoparticle interaction with gastrointestinal mucus and distribution in the gastrointestinal tract following oral and rectal administration in the mouse

“…Mucoadhesion purportedly allows the particulates to leave the chyme by adhering to the mucus layers lining the GI tract [8-10]. It is widely agreed that enhanced drug delivery from the chyme to the entire (highly-folded) GI tract epithelium, including the highly absorptive jejunum, where fluid absorption greatly speeds nutrient uptake, is desired for maximum absorption into the systemic circulation [8, 11-14].…”

Engineering of Δ 9 -tetrahydrocannabinol delivery systems based on surface modified-PLGA nanoplatforms

“…Unfortunately, the big size (in the micrometre range) of the drug delivery system limited its use to the parenteral route of administration [4,5]. As an alternative, nanometer-sized delivery systems based on poly(d,l-lactide-co-glycolide) (PLGA) were formulated for the oral administration of the cannabinoid receptor agonist 13 (CRA13 or CB-13), a potent synthetic cannabinoid drug which acts as an agonist agent at both the cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) [6,7], that is suitable for the treatment of neuropathic pain [8]. Some of the limitations to the oral administration of these PLGA nanoparticles (NPs) come from the physical chemistry of their surfaces: the negative surface charge may hinder their interaction with the gastrointestinal (GI) mucosa [6,9] and, if oral absorption takes place, the NPs can be rapidly recognized by the reticuloendothelial system (RES), as foreign entities, being then uptaken by macrophages (plasma clearance).…”

Understanding peroral absorption: regulatory aspects and contemporary approaches to tackling solubility and permeability hurdles

“…An ex vivo mucoadhesive study and Caco-2 uptake study revealed enhanced mucoadhesion and cell internalization for chitosan-modified PLGA nanoparticles. This may be due to electrostatic interactions between the positively charged surface of the nanoparticle and negatively charged mucin 97 . Andrographolide-loaded pH-sensitive nanoparticles prepared by using cationic poly-methacrylate copolymer have been shown to improve bioavailability 98 .…”