Dynamic Behavior of the Structural Phase Transition of Hydrogel Formation Induced by Temperature Ramp and Addition of Ibuprofen.

Understanding the dynamic behavior of hydrogel formation induced by a temperature ramp is essential for the design of gel-based injectable formulation as drug-delivery vehicles. In this study, the dynamic behavior of the hydrogel formation of Pluronic F108 aqueous solutions within different heating rates was explored in both macroscopic and microscopic views. It was discovered that when the heating rate is increased, the gelation temperature window (hard gel region) shrinks and the mechanical strength of the hydrogel decreases. A given system at different heating rates would lead to different crystalline structural evolutions. The time-resolved small-angle X-ray scattering (SAXS) experiments at a heating rate of 10 °C/min disclose that the crystalline structure of micelle packing in the hydrogel exhibits a series of transitions: hexagonal close-packed (HCP) to face-centered cubic (FCC) and body-centered cubic (BCC) structures coexisting and then to the BCC structure along with the increasing temperature. For the system at equilibrium, the BCC structure exclusively dominates the system. Furthermore, the addition of a hydrophobic model drug (ibuprofen) to the F108 aqueous solution promotes hard gel formation at even lower temperatures and concentrations of F108. The SAXS results for the system with ibuprofen at a heating rate of 10 °C/min demonstrate a mixture of FCC and BCC structures coexisting over the whole gelation window compared to the BCC structure that exclusively dominates the system at equilibrium. The addition of ibuprofen would alter the structural evolution to change the delivery path of the encapsulated drug, which is significantly related to the performance of drug release.

Small-Angle X-ray Scattering Studies on the Structure of Disc-Shaped Bicelles Incorporated with Neutral PEGylated Lipids.

In this study, small-angle X-ray scattering (SAXS) is successfully employed to investigate the structure of the DPPC/diC7PC disc-shaped bicelles incorporated with different amounts of C16-PEG2000-Ceramide lipids. The incorporation of the C16-PEG2000-Ceramide lipids could provide an antifouling capability to the bicelle for biomedical applications. However, traditionally it is believed that most of the incorporated PEGlylated lipids should lie in the rim of the disc-shaped bicelle. In this study, high sensitivity SAXS reveals the distribution of the added C16-PEG2000-Ceramide lipids in both the planar region and in the rim of the bicelle. The PEG brushes of C16-PEG2000-Ceramide lipids form a second shell outside the lipid headgroup shell of the bicelle. A double shell disc bicelle model is used in analyzing the SAXS data. The lipid density of C16-PEG2000-Ceramide in the rim is found to be about 1.7 times the C16-PEG2000-Ceramide lipid density in the planar region for all three C16-PEG2000-Ceramide concentrations, 1, 2, and 3 mM. Moreover, the bicelle core radius can be predicted well using the actual molecular ratio of lipids in the planar region to the lipids in the rim of the bicelles in the model calculation.

Revealing cholesterol effects on PEGylated HSPC liposomes using AF4-MALS and simultaneous small- and wide-angle X-ray scattering.

Liposome development is of great interest owing to increasing requirements for efficient drug carriers. The structural features and thermal stability of such liposomes are crucial in drug transport and delivery. Reported here are the results of the structural characterization of PEGylated liposomes via small- and wide-angle X-ray scattering and an asymmetric flow field-flow fractionation (AF4) system coupled with differential refractive-index detection, multi-angle light scattering (MALS) and dynamic light scattering. This integrated analysis of the exemplar PEGylated liposome formed from hydrogenated soy phosphatid-yl-choline (HSPC) with the addition of cholesterol reveals an average hydro-dynamic radius (R h) of 52 nm with 10% polydispersity, a comparable radius of gyration (R g) and a major liposome particle mass of 118 kDa. The local bilayer structure of the liposome is found to have asymmetric electronic density profiles in the inner and outer leaflets, sandwiched by two PEGylated outer layers ca 5 nm thick. Cholesterol was found to effectively intervene in lipid chain packing, resulting in the thickening of the liposome bilayer, an increase in the area per lipid and an increase in liposome size, especially in the fluid phase of the liposome. These cholesterol effects show signs of saturation at cholesterol concentrations above ca 1:5 cholesterol:lipid molar ratio.

Role of molecular weight and hydrophobicity of amphiphilic tri-block copolymers in temperature-dependent co-micellization process and drug solubility.

The binary P123 + F108, + F98, + F88, + F68, + F87 and + P84 systems were used to systematically explore the effect of molecular weight and hydrophobicity of Pluronic on the tendency of cooperative binding between parent copolymers and solubility of drug (ibuprofen) in these mixed Pluronic systems. Temperature-dependent co-micellization process in these systems was carefully investigated by using high sensitivity differential scanning calorimeter (HSDSC), dynamic light scattering (DLS) and small angle X-ray scattering (SAXS). All the HSDSC thermograms for these systems consistently exhibit two endothermic (micellization) peaks apart by at least 13.3 °C. It was evidenced that micelles are mainly formed by P123, the copolymer with a lower critical micelle temperature (CMT), at low temperatures. Raising temperature would dehydrate the other Pluronic with a higher CMT to be integrated into the neat P123 micelles developed at low temperatures. When the temperature is further increased beyond the second endothermic peak, the mixed micelles with a two-shell structure and characteristic corona lengths of their parent copolymers are observed to prove the existence of cooperative binding between parent copolymers. All the binary mixed Pluronic systems used in this study exhibit cooperative binding to form unimodal distribution of mixed micelles, except the P123 + F68 system. The SAXS results show that P123 + F68 system at 65 °C exhibits bimodal distribution of aggregates with coexisting of neat F68 micelles (65% in number) and P123 + F68 mixed micelles (35% in number). It is interesting to find out that P123 and F68 with distinct polypropylene oxide (PPO) moieties (i.e., a difference of 37 PO units) would exhibit very weak cooperative binding to partially form mixed micelles. Addition of ibuprofen in the P123 + F68 system would substantially enhance the cooperative binding between P123 and F68 to form bimodal distribution of aggregates with coexisting of neat F68 micelles (drops down to 30% in number) and P123 + F68 mixed micelles (increases up to 70% in number). For the systems with ibuprofen incorporated, SAXS results demonstrate that the drug is mainly encapsulated in the core of neat micelles developed at low temperatures. The solubility of ibuprofen in the 0.5 wt% P123 + 0.368 wt% P84 system is as high as 2.62 mg/ml, which is 114 times more than that in pure water at 37 °C.

The adsorption of DNA by cationic core-shell diblock copolymer polystyrene-block-poly(N-methyl 4-vinylpyridine iodide) micelles.

The diblock copolymer polystyrene-block-poly(N-methyl 4-vinylpyridine iodide) (PS-b-P4VPQ) with the molecular weight of PS 3.5 × 103 g/mol and P4VPQ 11.6 × 103 g/mol forms core-shell polymer micelles in aqueous solution. The cationic brush shell of the polymer micelle can be used to accommodate hydrophilic drugs and biomolecules, such as DNA, for biomedical applications. It is essential to understand how biomolecules are adsorbed within the brush layer. Here we investigated the interaction of the cationic brush of the polymer micelle with DNA by small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM). It is found when adding only relatively small amounts of on average 30 base pairs (bp) DNA, at 19.6 and 39.2 µM for 0.1 mM PS-b-P4VPQ, most of the polymer micelle/DNA complexes remain well dispersed. The brush layer of the polymer micelles are slightly swelled due to the adsorption of DNA within the brush layer. When the DNA concentration is increased to 58.8 µM or higher, the polymer micelle/DNA complexes form closely packed agglomerates. At high DNA concentrations, some adsorbed DNA will start to build up at the edge or surface of the brush layer which could induce aggregation of the polymer micelle/DNA complexes. This means that it is possible to prepare mostly dispersed polymer/DNA complexes by keeping the DNA concentration below the aggregation concentration. The well dispersed polymer micelle/DNA complexes are advantageous for many DNA related biomedical applications.