Search Results (6)

High-throughput permeation models are essential in drug development for timely screening of new drug and formulation candidates. Nevertheless, many current permeability assays fail to account for the presence of the gastrointestinal mucus layer. In this study, an optimised high-throughput mucus permeation model was developed employing a highly biorelevant mucus mimic. While mucus permeation is primarily conducted in a simple mucin solution, the complex chemistry, nanostructure and rheology of mucus is more accurately modelled by a synthetic biosimilar mucus (BSM) employing additional protein, lipid and rheology-modifying polymer components. Utilising BSM, equivalent permeation of various molecular weight fluorescein isothiocyanate-dextrans were observed, compared with native porcine jejunal mucus, confirming replication of the natural mucus permeation barrier. Furthermore, utilising synthetic BSM facilitated the analysis of free protein permeation which could not be quantified in native mucus due to concurrent proteolytic degradation. Additionally, BSM could differentiate between the permeation of poly (lactic-co-glycolic) acid nanoparticles (PLGA-NP) with varying surface chemistries (cationic, anionic and PEGylated), PEG coating density and size, which could not be achieved by a 5% mucin solution. This work confirms the importance of utilising highly biorelevant mucus mimics in permeation studies, and further development will provide an optimal method for high-throughput mucus permeation analysis. Full article

In this study, mucoactive self-emulsifying drug delivery systems (SEDDSs) based on sustained release of N-acetylcysteine (NAC) were developed for providing effective intestinal mucopermeation. Polymeric ionic complexes of NAC were formed with polyethyleneimine (PEI), Eudragit E 100, and Eudragit RS 100 and loaded into a novel SEDDS. The SEDDSs exhibited a stable average size of 75 ± 12 nm (polydispersity index (PDI) < 0.3) and showed a rise in the zeta potential from −17.31 mV to −7.72 mV. On Caco-2 cells, SEDDSs at 1–3% were non-cytotoxic. An average of 91.8 ± 5.4% NAC was released from SEDDSs containing Eudragit E 100 (p ≤ 0.05) and Eudragit RS 100 (p ≤ 0.001) complexes at a significantly slower rate within 80 min, whereas the SEDDS containing PEI released NAC in a matter of seconds. Similarly, the SEDDS complexes revealed a time-dependent reduction in mucus dynamic viscosity of 52.6 ± 19.9%. Consequently, as compared with a blank SEDDS, mucodiffusion revealed about 2- and 1.8-fold significantly greater mucopermeation of SEDDSs anchoring Eudragit E 100–NAC and RS 100–NAC complexes (p ≤ 0.05), respectively. The mucoactive SEDDSs, which steadily released NAC while permeating the mucus, were linked to a significantly increased mucopermeation in vitro as a result of optimal mucolytic targeting. Full article

Epithelial barriers separate the human body from the environment to maintain homeostasis. Compared to the skin and gastrointestinal tract, the respiratory barrier is the thinnest and least protective. The properties of the epithelial cells (height, number of layers, intercellular junctions) and non-cellular layers, mucus in the conducting airways and surfactant in the respiratory parts determine the permeability of the barrier. The review focuses on the non-cellular layers and describes the architecture of the mucus and surfactant followed by interaction with gases and pathogens. While the penetration of gases into the respiratory tract is mainly determined by their hydrophobicity, pathogens use different mechanisms to invade the respiratory tract. Often, the combination of mucus adhesion and subsequent permeation of the mucus mesh is used. Similar mechanisms are also employed to improve drug delivery across the respiratory barrier. Depending on the payload and target region, various mucus-targeting delivery systems have been developed. It appears that the mucus-targeting strategy has to be selected according to the planned application. Full article

Crosslinked chitosan nanocarriers (140–160 nm) entrapping coumarin-6 (λ_ex/em = 455/508 nm) with or without surface mannosylation were synthesized and assessed for cytotoxicity, adherence and cellular uptake in Caco-2 cells, flux across Caco-2 monolayers, and mucoadhesion to porcine mucin. Mannosylated and non-mannosylated nanocarriers demonstrated biocompatibility with slow release of coumarin-6 at pH 6.8 and 7.4 over 24 h. Adherence of the non-mannosylated nanocarriers (50 and 150 µg/mL) to Caco-2 cells was ~10% over 24 h, whereas cellular uptake of 25–30% was noted at 4 h. The mannosylated nanocarriers showed a similar adherence to non-mannosylated nanocarriers after 24 h, but a lower cellular uptake (~20%) at 1 h, comparable uptake at 4 h, and a higher uptake (~25–30%) at 24 h. Overall, the nanocarriers did not affect the integrity of Caco-2 monolayers. Mannosylated nanocarriers elicited higher P_app of 1.6 × 10⁻⁶ cm/s (50 µg/mL) and 1.2 × 10⁻⁶ (150 µg/mL) than the non-mannosylated ones: 9.8 × 10⁻⁷ cm/s (50 µg/mL) and 1.0 × 10⁻⁶ (150 µg/mL) after 2 h. Non-mannosylated chitosan nanocarriers elicited enhanced adhesion to porcine gut mucin via mucin-filled microchannels due to higher cationic charge density. These results underpin the importance of surface chemistry in the biological interactions of nanocarriers, while highlighting the role of surface hydrophilicity in mucopermeation due to mannosylation. Full article

P-glycoprotein (P-gP) efflux-mediated multidrug resistance is a fundamental aspect of chemotherapeutic failure in oncology. The current study aims to deliver paclitaxel (PTX) specifically at the target site with improved in vivo efficacy of poorly permeable PTX against solid tumors. Multifunctional polymeric micelles as targeted delivery have been devised for loading and release of PTX. Mucoadhesion, permeation enhancement, oral pharmacokinetics, biodistribution, and toxicological studies were carried out to fully elucidate the therapeutic outcomes of the polymeric micelles. Ex vivo permeation studies indicated a 7.89-fold enhancement in the permeation of PTX with mucopermeating papain functionalized thiolated redox micelles (PT-R-Ms) compared to the pure PTX. Moreover, PT-R-Ms exhibited a higher percentage of apoptotic cells (42.9 ± 0.07%) compared to pure PTX. Biodistribution studies revealed that fluorotagged PT-RMs accumulated in excised tumors and organs. The higher fluorescence intensity indicated the mucopermeation of micelles across the intestine. The orally administered PT-R-Ms efficiently overcome intestinal barriers and inhibit the P-gP efflux pump, resulting in increased bioavailability of PTX (up to 8-fold) in comparison to pure PTX. The enhanced anti-tumor efficacy and reduced toxic effects are key aspects of efficient cancer therapy. This study demonstrates that the use of mucopermeating PT-R-Ms is an encouraging approach to overwhelm the permeation barrier in cancer treatment. Full article

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. Full article