Dual-Acting Zeta-Potential-Changing Micelles for Optimal Mucus Diffusion and Enhanced Cellular Uptake after Oral Delivery

Abstract

Context: Overcoming the intestinal mucosal barrier can be a challenge in drug delivery. Nanoemulsions with negative zeta potentials can effectively permeate the mucus layer, but those with positive zeta potentials are better taken up by cells; a nanoemulsion with capricious zeta potential from negative to positive can achieve both good permeation and high uptake. Objective: This study aimed to develop dual-acting zeta-potential-amphoteric micelles enabling optimal muco-permeation and enhancement of cellular uptake. Methods: A micellar pre-concentrate was prepared from 15% Labrasol, 15% Kolliphor EL, 30% Kolliphor RH 40, and 40% dimethylsulfoxide. The micellar pre-concentrate was loaded with anionic stearic acid (SA), forming ionic complexes with cationic polymers at a ratio of 25:1 with Eudragit RS 100 and Eudragit RL 100. Blank micelles and those containing complexes were separately diluted in physiological buffers and examined for their droplet sizes, polydispersity indices (PDIs), zeta potentials, and cytotoxicity. The SA release from the micellar complexes was evaluated in 0.1 mM phosphate buffer (pH 6.8) containing 0.001% fluorescein, thereby enabling an instant decrease in fluorescence. Finally, the micelles were loaded with the model drug fluorescein diacetate (FDA) and evaluated for their muco-permeation behavior and cellular uptake. Results: The micellar dilutions formed micelles at the critical micelle concentration (CMC) of 312 µg/mL and showed a uniform average droplet size of 14.2 nm, with a PDI < 0.1. Micellar dilutions were non-cytotoxic when used at 1:100 in a physiological medium. Micelles loaded with ionic complexes achieved a sustained release of 95.5 ± 3.7% of the SA in 180 min. Moreover, the zeta potential of the complex-loaded micelles shifted from −5.4 to +1.8 mV, whereas the blank micelles showed a stabilized zeta potential of −10 mV. Furthermore, the negatively charged blank and complex-loaded micelles exhibited comparable muco-permeation, with an overall average of 58.2 ± 3.7% diffusion of FDA. The complex-loaded micellar droplets, however, provided a significantly higher cellular uptake of the model drug FDA (2.2-fold, p ≤ 0.01) Conclusion: Due to undergoing a shift in zeta potential, the modified micelles significantly enhanced cellular uptake while preserving mucus-permeating properties.

Lyophilized Nasal Inserts of Atomoxetine HCl Solid Lipid Nanoparticles for Brain Targeting as a Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD): A Pharmacokinetics Study on Rats

“…Atomoxetine-loaded SLNs formulae containing stearic acid had significantly higher negative ZP and lower PDI than the formulae containing Compritol 888 ATO according to the ANOVA test results ( p = 0.0143 and 0.0552 for effect of lipid type (X1) on ZP and PDI, respectively). The higher negative ZP is attributed to the negative charge of stearic acid obtained from the carboxylic acid moiety oriented in the hydrophilic surface of nanoparticles [ 29 ]. As shown in Figure 4 , it was also found that using lower co-surfactant ratio of span 60: Pluronic f127 of (1:3) enhanced the stability of the formed pre-emulsion and decreased the tendency of the nanoparticles to aggregate ( p -value = 0.0053) [ 24 ].…”

Strategies to Enhance the Solubility and Bioavailability of Tocotrienols Using Self-Emulsifying Drug Delivery System

“…Therefore, dual-acting zeta-potential micelles were designed to achieve optimal muco-permeation and cellular uptake. Through slow and time-dependent changes in zeta potentials, micellar droplets provide optimal mucus permeation and significant cellular uptake [118].…”

Polymers Enhancing Bioavailability in Drug Delivery

“…The intestinal mucosal barrier poses a challenge in oral drug delivery, and the development of dual-acting zeta-potential-amphoteric micelles has been proposed to overcome it, by allowing optimal mucopermeation and enhancing cellular uptake [ 7 ]. The rationale of the work is that, since the zeta potential of nanoemulsions is known to influence both parameters in opposite directions (cellular uptake is promoted by positively charged and permeation by negatively charged nanodroplets), a system capable of zeta-potential shifting would be beneficial.…”