The effect of dendrimer generations on the structure of Q(G) LLC mesophase and drug release.

In this paper the cosolubilization of 2nd, 3rd, and 4th generations of polypropyleneimine (PPI: PPI-G2, -G3, and -G4) dendrimers with sodium diclofenac (Na-DFC) into reverse gyroid cubic (Q(G)) liquid crystals is reported. Structural properties and interactions of PPI dendrimers with and without the drug were studied using small-angle X-ray scattering, attenuated total reflected Fourier transform infrared (ATR-FTIR) spectroscopy, and differential scanning calorimetry (DSC) measurements. Incorporation of PPI-G2 (without Na-DFC) into Q(G) mesophase led to a decrease of 78Å in the lattice parameter. Solubilization of higher PPI generations, G3 and G4, led to increases in the lattice parameter to 57Å and 64Å, respectively. At 25wt%, each of the dendrimers caused a phase transition Q(G)→reverse hexagonal (HII). According to ATR-FTIR and DSC, the large lattice parameter values of G3 and G4 (relative to G2) embedment were assigned to their interactions with the carboxyl groups of GMO at the interface in comparison to the strong interaction of PPI-G2 with the water. Cosolubilization of Na-DFC with PPI-G2 revealed enlargement of the lattice parameter (of the new HII mesophase), while in the case of G3 and G4 systems no significant influence was seen with Na-DFC. The release of Na-DFC from Q(G) and HII systems was followed by UV-vis spectroscopy and revealed generation-dependence on drug release. As dendrimer generation increased, the cumulative drug release decreased.

Reversed hexagonal lyotropic liquid-crystal and open-shell glycodendrimers as potential vehicles for sustained release of sodium diclofenac.

The effect of second, third, and fifth generations of poly(propylene imine) glycodendrimers-open maltose shell (PPI-Mal) on reverse hexagonal (HII) mesophase and on the release of sodium diclofenac (Na-DFC) drug was investigated. The HII mesophase comprised glycerol monooleate (GMO)/tricaprylin (TAG) in a weight ratio of 90/10 and 20 wt % water (+0.5 wt % PPI-Mal of each generation) without or with 0.25 wt % (Na-DFC). The microstructural characteristics of these systems were determined by small-angle X-ray scattering; attenuated total reflectance Fourier transform infrared was used to characterize the molecular level interactions and the location of the PPI-Mal. Third-and fifth-generation PPI-Mal, because of their maltose groups, interact mainly with the bulk water within the cylinders of the HII and strongly bind the water molecules, as manifested by the decrease in the lattice parameter and dehydration of the lipid headgroups. Co-solubilization of Na-DFC with the third and fifth generations caused competition of the two host compounds for water binding and induced relocation of the drug from the bulk water to the GMO-water interface. In vitro release of Na-DFC from the HII showed that the release process was faster in the systems with third- and fifth-generation PPI-Mal compared with the control and second-generation systems.

Structural characterization of lyotropic liquid crystals containing a dendrimer for solubilization and release of gallic acid.

The role of 2nd generation polypropyleneimine (PPIG2) dendrimer in controlling the release of gallic acid (GA) as a model drug from lyotropic liquid crystal was explored. GA (0.2wt%) was solubilized in three types of mesophases: lamellar (Lα), cubic (space group of Ia3d, Q(G)), and reverse hexagonal (HII), composed of GMO and water (and d-α-tocopherol, or tricaprylin in the case of HII mesophases). Small angle X-ray scattering (SAXS) and attenuated total reflectance Fourier transform infrared (ATR-FTIR) along with UV spectrophotometry were utilized to elucidate the structure modifications and release resulting from the cosolubilization of GA and PPIG2. Solubilization of PPIG2 into Lα and Q(G) phases caused transformation of both structures to HII. The diffusion of GA out of the mesophases was found to be dependent on water content and PPIG2 concentration. Rapid release from Lα+PPIG2 and Q(G)+PPIG2 mesophases was recorded. The release from both HII mixtures (with d-α-tocopherol and tricaprylin) was shown to be dependent on the type of oil. Release studies conducted for 72h showed that GA release can be modulated and sustained by the presence of PPIG2, supposedly due to the electrostatic interactions between the dendrimer and the drug molecule.

Structural behavior and interactions of dendrimer within lyotropic liquid crystals, monitored by EPR spectroscopy and rheology.

Micro- and macrostructural behaviors of three different lyotropic liquid crystals (LLCs) loaded with a dendrimer, namely second generation poly(propylene imine) (PPI-G2), were studied by means of rheology and electron paramagnetic resonance (EPR). The three mesophases were L(α), Q(224), and H(II) composed of glycerol monooleate (GMO) and water-PPI-G2 solution (and d-α-tocopherol (vitamin E) in the case of H(II)). We characterized the impact of PPI-G2 interactions with the components of the host mesophases on their structural characteristics on different length scales. The incorporation of PPI-G2 within the L(α) and H(II) systems induced the formation of more elastic hexagonal systems with a "solidlike" behavior, while in the Q(224) system a different trend with a "liquidlike" behavior was observed. As a result, the dendrimer induced a remarkable change in both the structural and viscoelastic properties of the systems. Hence, the microenvironment in the interface region within the systems was monitored by computer-aided EPR using 5-doxylstearic acid (5-DSA) as a pH-dependent probe. The microviscosity (τ) and order (S) of systems were found to be sensitive to the PPI-G2 presence: when PPI-G2 concentration increased, τ and S increased in both the L(α) and Q(224) systems. In the H(II) systems two trends were observed, reflecting a decrease in τ and S up to 10 wt % PPI-G2 and subsequently their increase at higher dendrimer concentrations. It was assessed that PPI-G2 interacted strongly with the GMO hydroxyl groups in the L(α) phase, with the water molecules in the Q(224) systems. In the H(II) mesophase strong interactions with both the water and GMO hydroxyl molecules were detected.

Complex dendrimer-lyotropic liquid crystalline systems: structural behavior and interactions.

The incorporation of dendrimer into three lyotropic liquid crystalline (LLCs) mesophases is demonstrated for the first time. A second generation (G2) of poly(propylene imine) dendrimer (PPI) was solubilized into lamellar, diamond reverse cubic, and reverse hexagonal LLCs composed of glycerol monooleate (GMO), and water (and D-α-tocopherol in the H(II) system). The combination of PPI with LLCs may provide an advantageous drug delivery system. Cross-polarized light microscope, small-angle X-ray scattering (SAXS), and attenuated total reflectance Fourier transform infrared (ATR-FTIR) were utilized to study the structural behavior of the mesophases, the localization of PPI within the system, and the interactions between the guest molecule and the system's components. It was revealed that PPI-G2 functioned as a "water pump", competing with the lipid headgroups for water binding. As a result, L(α)→H(II) and Q(224)→H(II) structural shifts were detected (at 10 wt % PPI-G2 content), probably caused by the dehydration of monoolein headgroups and subsequent increase of the lipid's critical packing parameter (CPP). In the case of H(II), as a result of the balance between the dehydration of the monoolein headgroups and the significant presence of PPI within the interfacial region, increasing the quantity of hydrogen bonds, no structural transitions occurred. ATR-FTIR analysis demonstrated a downward shift of the H-O-H (water), as a result of PPI-G2 embedment, suggesting an increase in the mean water-water H-bond angle resulting from binding PPI-G2 to the water network. Additionally, the GMO hydroxyl groups at ß- and γ-C-OH positions revealed a partial interaction of hydrogen bonds with N-H functional groups of the protonated PPI-G2. Other GMO interfacial functional groups were shown to interact with the PPI-G2, in parallel with the GMO dehydration phenomenon. In the future, these outcomes can be used to design advanced drug delivery systems, allowing administration of dendrimers as a therapeutic agent from LLCs.

Solubilization of vitamin E into H(II) LLC mesophase in the presence and in the absence of vitamin C.

The synergistic solubilization of two major hydrophilic (vitamin C, ascorbic acid, AA) and lipophilic (vitamin E, D-alpha-tocopherol, VE) antioxidants within reverse hexagonal (H(II)) mesophases is reported. The H(II) mesophases are composed of monoolein (GMO)/VE/AA/water. A wide range of VE concentration was examined (on the expense of GMO concentrations) while the AA and water concentrations remained constant (4 and 12.5 wt %, respectively) in order to expand the H(II) mesophase. SAXS and DSC combined with ATR-FTIR techniques were utilized to study the interactions between each solubilizate and the H(II) component that enabled the synergistic accommodation of the hydrophilic and hydrophobic molecules. It was revealed that up to 27 wt % VE solubilized within the H(II) mesophase. This hydrophobic additive localized at the lipophilic GMO tail region solvating the surfactant tails, thereby enabling the formation of the H(II) structure. As a result, the lattice parameter and the melting point of the hydrophobic tails decreased. Above 27 wt % VE (up to 33 wt %), once the GMO lipophilic region was homogenously solvated, additional VE molecules located closer to the interface. At this range of concentrations, new hydrogen bonds between O-H groups of VE and O-H groups of GMO were formed. Once 35 wt % VE was introduced, the H(II) structure transformed to face-centered reverse micellar cubic phase (Fd3m, Q(227)).

Structural rearrangements and interaction within H(II) mesophase induced by cosolubilization of vitamin E and ascorbic acid.

We investigated the effect of ascorbic acid (AA) cosolubilized with vitamin E (VE) on reverse hexagonal (H(II)) mesophase. The H(II) phase comprises monoolein (GMO)/d-alpha-tocopherol (VE) in a ratio of 90/10 by weight and 12.5 wt % water. The macrostructural characteristics of this system were determined by polarized light microscopy and small-angle X-ray scattering measurements. We used differential scanning calorimetry and attenuated total reflectance Fourier transform infrared to characterize the microstructure, the vibration of the functional groups, and the location of the AA guest molecule. AA was incorporated to the system in two steps: 1-4 wt % AA and 5-6 wt % AA. We compared this system to one containing tricaprylin as the oil phase, as previously reported. These measurements revealed that AA is localized first in the water rich-core and in the interface, and acts as a chaotropic molecule that decreases the water melting point. When a larger quantity of AA (5-6 wt %) is added, the system is saturated, and the AA is located in the inner cylinder and manifested by more moderate distortion. The addition of AA also causes alteration in the behavior of the GMO hydrocarbon chains and makes them more flexible. Further addition of AA caused the GMO hydrocarbon chain to be more solvated by the VE hydrocarbon chain and enabled additional migration of VE; hence a decrease in the hydrophobic melting temperature occurred (similar to tricaprylin). Increasing the amount of AA weakened the bonding between the GMO and water and created new bonds between AA and GMO and AA with water.