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

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.

Structure and Synthesis of Dihalogenodicyanoaurate Complexes [Ph3PR][Au(CN)2Hal2], Hal = Cl, R = Me, СH2Ph; Hal = Br, R = cyclo-C6H11; Hal = I, R = Ph

Interaction of organyltriphenylphosphonium halides with potassium dihalogenodicyanoaurates in water followed by recrystallization of reaction products from acetonitrile or DMSO has been used to synthesize gold(III) ionic complexes [Ph3PMe][Au(CN)2Cl2] (1), [Ph3PCH2Ph][Au(CN)2Cl2] (2), [Ph3PC6H11-cyclo][Au(CN)2Br2] (3), and [Ph4P][Au(CN)2I2] (4), which have been structurally characterized by the X-ray analysis method (CIF files CCDC No. 1901681 (1), 1912903 (2), 1912919 (3), 2048146 (4)). According to the X-ray data crystals 1–4 consist of centrosymmetric square-planar [Au(CN)2Hal2]– anions (the Au–Hal average bond lengths are 2.417(3) Å (1), 2.280(2) Å (2), 2.4203(13) Å (3), and 2.6035(10) Å (4); the Au–C average bond lengths are 2.06(2) Å (1), 2.010(7) Å (2), 2.009(7) Å (3,) and 1.998(6) Å (4)); the phosphorus atoms in organyltriphenylphosphonium cations have a slightly distorted tetrahedral coordination (the P–C bond lengths are 1.782(9)-1.806(8) Å (1), 1.788(4)-1.813(5) Å (2), 1.790(5)-1.813(5) Å (3) and 1.793(6)-1.799(5) Å (4)). The structural organization in crystals 2–4 is caused by the interionic С–H∙∙∙N≡C hydrogen bonds (C–HPh∙∙∙N≡C 2.56 Å (2); C–HPh∙∙∙N≡C 2.43–2.59 Å, C–Hcyclohexyl∙∙∙N≡C 2.47 Å (3), C–HPh∙∙∙N≡C 2.63 Å (4)), while in crystals 1 no significant interionic contacts are observed.

Structural diversity of salts of terpyridine derivatives with europium(III) located in both, cation and anion, in comparison to molecular complexes

Three salts of the common composition [EuCl2(X-tpy)2][EuCl4(X-tpy)]·nMeCN were obtained from EuCl3·6H2O and the respective organic ligands (X-tpy = 4′-phenyl-2,2′:6′,2″-terpyridine ptpy, 4′-(pyridin-4-yl)-2,2′:6′,2″-terpyridine 4-pytpy, and 4′-(pyridin-3-yl)-2,2′:6′,2″-terpyridine 3-pytpy). These ionic complexes are examples of salts, in which both cation and anion contain Eu3+ with the same organic ligands and chlorine atoms coordinated. As side reaction, acetonitrile transforms into acetamide resulting in the crystallization of the complex [EuCl3(ptpy)(acetamide)] (4). Salts [EuCl2(ptpy)2][EuCl4(ptpy)]·2.34MeCN (1), [EuCl2(4-pytpy)2][EuCl4(4-pytpy)]·0.11MeCN (2), and [EuCl2(3-pytpy)2][EuCl4(3-pytpy)]·MeCN (3) crystallize in different structures (varying in space group and crystal packing) due to variation of the rear atom of the ligand to a coordinative site. Additionally, we show and compare structural variability through the dimeric complexes [Eu2Cl6(ptpy)2(N,N′-spacer)]·N,N′-spacer (5, 6, 7) obtained from [EuCl3(ptpy)(py)] by exchanging the end-on ligand pyridine with several bipyridines (4,4′-bipyridine bipy, 1,2-bis(4-pyridyl)ethane bpa, and 1,2-bis(2-pyridyl)ethylene bpe). In addition, photophysical (photoluminescence) and thermal properties are presented.

Tripodal Podand Ligand with a Superhalogen Nature as an Effective Molecular Trap

Tris(2-methoxyethyl) fluoroborate anion (TMEFA), anovel tripodal ligand based on the BF4− superhalogen anion, is proposed and was investigated theoretically using ab initio MP2 (second-order Møller-Plesset perturbational method) and OVGF (outer valence Green function) methods. The studied molecule comprises three 2-methoxyethoxy groups (-O-CH2-CH2-O-CH3) connected to a central boron atom, which results in the C3-symmetry of the compound. The resulting anion was stable against fragmentation processes and its vertical electron detachment energy was found to be 5.72 eV. Due to its equilibrium structure resembling that of classical tripodal podands, the [F-B(O-CH2-CH2-O-CH3)3]− anion is capable of binding metal cations using its three arms, and thus may form strongly bound ionic complexes such as [F-B(O-CH2-CH2-O-CH3)3]−/Li+ and [F-B(O-CH2-CH2-O-CH3)3]−/Mg2+. The binding energies predicted for such compounds far exceed those of the similar neutral classical podand ligands, which likely makes the [F-B(O-CH2-CH2-O-CH3)3]− system a more effective molecular trap or steric shielding agent with respect to selected metal cations.

Formulation of Lipoprotein Microencapsulated Beadlets by Ionic Complexes in Algae-Based Carbohydrates

The present study aims to produce sustained-release algae-based carbohydrate microbeadlets of lipoproteins rich-in carotenoids extracted from organic sea buckthorn fruits. β-carotene represented the major compound of the lipoproteins extracts. Emulsification and algae-based carbohydrates, such as sodium-alginate and kappa-carrageenan, provide an inert environment, allowing the embedded targeted bioactive compounds—lipoproteins rich in carotenoids in our case—to maintain greater biological activity and to have a better shelf life. Furthermore, the microbeadlets prepared from sodium-alginate–kappa-carrageenan (0.75%:0.75% w/v) crosslinked with calcium ions showing 90% encapsulation efficiency have been utilized in HPMC capsules using beadlets-in-a-capsule technology, to use as a delivery system for the finished product. The GI simulated tests performed under laboratory conditions suggested that the sodium-alginate–kappa–carrageenan combination could be useful for the formulation-controlled release of microbeadlets containing lipoproteins rich in carotenoids.