Role of Polyanions and Surfactant Head Group in the Formation of Polymer-Colloid Nanocontainers.

OBJECTIVES: This study was aimed at the investigation of the supramolecular systems based on cationic surfactants bearing cyclic head groups (imidazolium and pyrrolidinium) and polyanions (polyacrylic acid (PAA) and human serum albumin (HSA)), and factors governing their structural behavior to create functional nanosystems with controlled properties. Research hypothesis. Mixed PE-surfactant complexes based on oppositely charged species are characterized by multifactor behavior strongly affected by the nature of both components. It was expected that the transition from a single surfactant solution to an admixture with PE might provide synergetic effects on structural characteristics and functional activity. To test this assumption, the concentration thresholds of aggregation, dimensional and charge characteristics, and solubilization capacity of amphiphiles in the presence of PEs have been determined by tensiometry, fluorescence and UV-visible spectroscopy, and dynamic and electrophoretic light scattering. RESULTS: The formation of mixed surfactant-PAA aggregates with a hydrodynamic diameter of 100-180 nm has been shown. Polyanion additives led to a decrease in the critical micelle concentration of surfactants by two orders of magnitude (from 1 mM to 0.01 mM). A gradual increase in the zeta potential of HAS-surfactant systems from negative to positive value indicates that the electrostatic mechanism contributes to the binding of components. Additionally, 3D and conventional fluorescence spectroscopy showed that imidazolium surfactant had little effect on HSA conformation, and component binding occurs due to hydrogen bonding and Van der Waals interactions through the tryptophan amino acid residue of the protein. Surfactant-polyanion nanostructures improve the solubility of lipophilic medicines such as Warfarin, Amphotericin B, and Meloxicam. PERSPECTIVES: Surfactant-PE composition demonstrated beneficial solubilization activity and can be recommended for the construction of nanocontainers for hydrophobic drugs, with their efficacy tuned by the variation in surfactant head group and the nature of polyanions.

Therapy of Organophosphate Poisoning via Intranasal Administration of 2-PAM-Loaded Chitosomes.

Chitosan-decorated liposomes were proposed for the first time for the intranasal delivery of acetylcholinesterase (AChE) reactivator pralidoxime chloride (2-PAM) to the brain as a therapy for organophosphorus compounds (OPs) poisoning. Firstly, the chitosome composition based on phospholipids, cholesterol, chitosans (Cs) of different molecular weights, and its arginine derivative was developed and optimized. The use of the polymer modification led to an increase in the encapsulation efficiency toward rhodamine B (RhB; ~85%) and 2-PAM (~60%) by 20% compared to conventional liposomes. The formation of monodispersed and stable nanosized particles with a hydrodynamic diameter of up to 130 nm was shown using dynamic light scattering. The addition of the polymers recharged the liposome surface (from -15 mV to +20 mV), which demonstrates the successful deposition of Cs on the vesicles. In vitro spectrophotometric analysis showed a slow release of substrates (RhB and 2-PAM) from the nanocontainers, while the concentration and Cs type did not significantly affect the chitosome permeability. Flow cytometry and fluorescence microscopy qualitatively and quantitatively demonstrated the penetration of the developed chitosomes into normal Chang liver and M-HeLa cervical cancer cells. At the final stage, the ability of the formulated 2-PAM to reactivate brain AChE was assessed in a model of paraoxon-induced poisoning in an in vivo test. Intranasal administration of 2-PAM-containing chitosomes allows it to reach the degree of enzyme reactivation up to 35 ± 4%.

Mitochondria-targeted mesoporous silica nanoparticles noncovalently modified with triphenylphosphonium cation: Physicochemical characteristics, cytotoxicity and intracellular uptake.

Novel nanocomposite system based on mesoporous silica nanoparticles (MSNs) noncovalently modified with hexadecyltriphenylphosphonium bromide (HTPPB) has been prepared, thoroughly characterized and used for encapsulation of model cargo Rhodamine B (RhB). The high encapsulation efficacy of this dye by HTPPB-modified mesoporous particles was demonstrated by spectrophotometry and thermography techniques. The bioavailability of MSN@HTPPB was testified. Cytotoxicity assay revealed that a marked suppression of M-HeLa cancer cells (epithelioid carcinoma of the cervix) occurs at concentration of 0.06 µg/mL, while the higher viability of Chang liver normal cell line was preserved in the concentration range of 0.98-0.06 µg/mL. Hemolysis assay demonstrated that only 2% of red blood cells are destructed at ~ 30 µg/mL concentration. This allows us to select the most harmless compositions based on MSN@HTPPB with minimal side effects toward normal cells and recommend them for the development of antitumor formulations. Fluorescence microscopy technique testified satisfactory penetration of HTPPB-modified carriers into M-HeLa cells. Importantly, modification of the MSN with HTPPB is shown to promote efficient delivery to mitochondria. To the best of our knowledge, it is one of the first successful examples of noncovalent surface modification of the MSNs with lipophilic phosphonium cation that improves targeted delivery of loads to mitochondria.

Self-Assembled Quaternary Ammonium-Containing Comb-Like Polyelectrolytes for the Hydrolysis of Organophosphorous Esters: Effect of Head Groups and Counter-Ions.

The aim of this work was to increase the efficiency of catalytic systems for the hydrolytic cleavage of 4-nitrophenyl esters of phosphonic acids. Quaternary ammonium-containing comb-like polyelectrolytes («polymerized micelles¼) with ester cleavable fragments and a low aggregation threshold were used as catalysts. The synthesis of poly(11-acryloyloxyundecylammonium) surfactants with different counterions (Br- , NO3- , CH3 C6 H4 SO3- ) and head groups was realized by micellar free-radical polymerization. Molecular weight, critical association concentration, particle sizes and solubilization properties toward Orange OT were determined. Self-assemblies organized by poly(11-acryloyloxyundecyltrimethyl ammonium) bromide successfully catalyze the hydrolysis of 4-nitrophenyl butylchloromethylphosphonate up to two orders of magnitude compared to aqueous alkaline hydrolysis. The development of these catalysts is promising for industrial applications and organophosphorus compound detoxification.

Multi-targeted approach by 2-benzimidazolylquinoxalines-loaded cationic arginine liposomes against сervical cancer cells in vitro.

Multi-targeted approaches for inhibition of сervical cancer cells in vitro were developed by implementing two different strategies and drug combination for creation of new therapeutic target agents and for nanotechnological-enhancement of intracellular delivery. New 2-benzimidazolylquinoxalines derivatives were synthesized and characterized by combining two different pharmacophores - benzimidazole and quinoxaline rings directly bonded in their structures. Spectrophotometric technique for determination of content of compounds in various media was developed to evaluate their solubility in water and micellar solutions of surfactants. The bioavailability of poorly water-soluble 2-benzimidazolylquinoxalines was improved by PEGylated liposomes as antitumor drug delivery carriers. 2-benzimidazolylquinoxalines-loaded PEGylated liposomes, with size close to 100 nm and negative zeta potential ranging from -13 mV to -27 mV, were time-stable at room temperature. The design of liposomal formulations for improving cellular uptake and in vitro antitumor efficacy was performed by modification of liposome surface with the new arginine surfactant. The cell viability of 2-benzimidazolylquinoxalines-loaded arginine liposomes on human cancer M-Hela cells was 16% at the concentration 0.15 mg/ml. Moreover, these liposomes showed a lower toxicity (40%) against normal human Gang liver cells both at the lowest and highest tested concentrations.

Self-assembling systems based on amphiphilic alkyltriphenylphosphonium bromides: elucidation of the role of head group.

A systematic study of the aggregation behavior of alkyltriphenylphosphonium bromides (TPPB-n; n=8, 10, 12, 14, 16, 18; here n is the number of carbon atoms in alkyl groups) in aqueous solutions has been carried out and compared with trimethyl ammonium bromides (TMAB-n). Critical micelle concentrations (cmcs) of TPPB-n and TMAB-n decrease with the number of carbon atoms with the slope parameter of ca.0.3. The low cmcs and effective solubilization power toward Orange OT indicate high micellization capacity of phosphonium surfactants. The low counterion binding parameter ß is revealed for TPPB-10 and TPPB-12, while high counterion binding of ≥80% is observed for high TPPB-n homologs. Values of the surface potential ψ calculated on the basis of pK(a) shifts of p-nitrophenols is similar for both series and monotonously increase with alkyl chain length. Several points indicate non-monotonic changes within TPPB-n series. There are peculiarities of the tensiometry and solubilization plots for high homologs and above mentioned increases in counterion binding on transiting from low to high molecular weight surfactants. Differences in aggregation behavior between TPPB and TMAB series and between low and high homologs can be due to the specific structural character of the TPP(+) cation, which is supported by X-ray data.

Novel bolaamphiphilic pyrimidinophane as building block for design of nanosized supramolecular systems with concentration-dependent structural behavior.

A new macrocyclic bolaamphiphile with thiocytosine fragments in the molecule (B1) has been synthesized and advanced as perspective platform for the design of soft supramolecular systems. Strong concentration-dependent structural behavior is observed in the water-DMF (20% vol) solution of B1 as revealed by methods of tensiometry, conductometry, dynamic light scattering, and atomic force microscopy. Two breakpoints are observed in the surface tension isotherms. The first one, around 0.002 M, is identified as a critical micelle concentration (cmc), whereas the second critical concentration of 0.01 M is a turning point between the two models of the association involved. Large aggregates of ca. 200 nm are mostly formed beyond the cmc, whereas small micelle-like aggregates exist above 0.01 M. The growth of aggregates between these critical points occurs, resulting in a gel-like behavior. An unusual decrease in the solution pH with concentration takes place, which is assumed to originate from the steric hindrance around the B1 head groups. Because of controllable structural behavior, B1 is assumed to be a candidate for the development of biomimetic catalysts, nanocontainers, drug and gene carriers, etc.

Nanoreactors based on amphiphilic uracilophanes: self-organization and reactivity study.

New amphiphilic pyrimidinic macrocycles (APMs) with two (APM-1) and three (APM-2) decyl tails have been synthesized by quaternization of the bridged N. Complex examination of the APM-based systems with the help of tensiometry, conductometry, dynamic light scattering, and UV and NMR spectroscopy provides evidence for their aggregation. Calculations based on surface tension isotherms and on packing parameter considerations make it possible to assume a lamellar packing of macrocycles when aggregating. Marked differences in the aggregation behavior of APM-1 and APM-2 have been found. The additives of polyethylenimine (PEI) exert little influence on the critical micelle concentration (cmc) of APM-1, while in the APM-2/PEI systems there occurs a pronounced decrease in the cmc and also a ca. 2-fold decrease in the surface area per molecule. The APM-based assemblies are explored as nanoreactors for the hydrolysis of O-alkyl O-p-nitrophenyl (chloromethyl)phosphonates (alkyl = ethyl, hexyl). The kinetic study reveals a minor rate effect of the APM-1-based systems. In the APM-2-based systems an acceleration of the hydrolysis of both phosphonates occurs as compared to the uncatalyzed process. Within the APM-2 --> APM-2/PEI --> APM-2/PEI/La(III) series, due to the cooperative contributions of the supramolecular, polymer, and homogeneous catalysis, an increase in the catalytic effect is observed from 30 times to 3 orders of magnitude as compared to that of the basic hydrolysis of the substrates.

Nanosized reactors based on polyethyleneimines: from microheterogeneous systems to immobilized catalysts.

Effective nanoreactors based on polyethyleneimines (PEIs) for the hydrolytic cleavage of O-alkyl O-p-nitrophenyl chloromethylphosphonates (alkyl = ethyl, hexyl) and di(p-nitrophenyl)phosphate were developed in conformity with the idea of modeling the polyfunctional catalytic mechanism of enzymes. A step-by-step modification of the single PEI solution by additives with their own catalytic activities (sodium dodecyl sulfate and lanthanum salt) gave rise to a marked improvement in the reaction efficiency. A 104-106-fold acceleration of the reaction compared to the aqueous basic hydrolysis of the substrates was achieved in the sodium dodecyl sulfate-polyethyleneimine-La(III) ternary system. This system can be considered to be metallomicelles immobilized on a hydrophilic polymer matrix. When the PEI immobilized on silica gel was used as a catalyst, the full completion of the reaction was achieved for 100 min under mild conditions, while the half-life of the reaction in a comparable homogeneous regime exceeds 100 h.