Amine-Functionalized CO₂ Responsive Triblock Copolymer MicellesA Small-Angle X‑ray Scattering Study

CO₂ responsive colloids are of interest for the delivery of active molecules in both pharmaceutical applications and for gas treatment technologies, among others. Primary and secondary organic amines react with CO₂ gas in aqueous solution to form ionic carbamates in an exothermic “CO₂ sequestration” reaction. Several amines important in this context are 2-aminoethanol, 2,2′-iminodiethanol, and piperazine. We have used small-angle X-ray scattering at a high intensity synchrotron source to demonstrate that triblock copolymer micelles containing carbamate-forming amines change shape upon exposure to CO₂. Modeling of the scattering data is used to elucidate the effects of exposure on micelle size and morphology. Electron density distribution within the micelles, derived from the SAXS data, established that the amines interact with the polymer micelles. The products of CO₂ exposure, namely, carbamate, bicarbonate anions, and protons, modify the packing of the polymer chains, and occupy the volume within the polymer aggregates. Our findings contribute to the detailed understanding and optimization of liquid based CO₂-responsive systems

Understanding the Mechanism of Enzyme-Induced Formation of Lyotropic Liquid Crystalline Nanoparticles

Liquid crystalline nanoparticles have shown great potential for application in fields of drug delivery and agriculture. However, optimized approaches to generating these dispersions have long been sought after. This study focused on understanding the mechanism of formation of cubosomes during the recently reported enzymatic approach and extending the approach to alternative lipid types other than phytantriol. The chain length of digestible lipids was found to influence the effectiveness of triglycerides in disrupting the equilibrium cubic phase structure to form the emulsion precursor. In general, a greater hydrophobicity of the triglyceride required a lower concentration to inhibit liquid crystal structure formation. Selachyl alcohol was also examined due to its nondigestible trait and ability to form the inverted hexagonal phase. Digestion of its precursor emulsion formed hexosomes analogous to the phytantriol-based systems. Finally, the assumption that fatty acids liberated during digestion needed to partition out of the nondigestible lipids for the re-formation of the phase structure was found to be untrue. Their ionization state, however, did have an effect on the resulting nanostructure, and this unique property could potentially provide a useful attribute for oral drug delivery systems

pH-Driven Colloidal Transformations Based on the Vasoactive Drug Nicergoline

The structure of colloidal self-assembled drug delivery systems can be influenced by intermolecular interactions between drug and amphiphilic molecules, and is important to understand in the context of designing improved delivery systems. Controlling these structures can enable controlled or targeted release systems for poorly water-soluble drugs. Here we present the interaction of the hydrophobic vasoactive drug nicergoline with the internal structure of nanostructured emulsion particles based on the monoglyceride–water system. Addition of this drug leads to modification of the internal bicontinuous cubic structure to generate highly pH-responsive systems. The colloidal structures were characterized with small-angle X-ray scattering and visualized using cryogenic transmission electron microscopy. Reversible transformations to inverse micelles at high pH, vesicles at low pH, and the modification of the spacing of the bicontinuous cubic structure at intermediate pH were observed, and enabled the <i>in situ</i> determination of an apparent p<i>K</i>_a for the drug in this systema difficult task using solution-based approaches. The characterization of this phase behavior is also highly interesting for the design of pH-responsive controlled release systems for poorly water-soluble drug molecules

Implications of the Digestion of Milk-Based Formulations for the Solubilization of Lopinavir/Ritonavir in a Combination Therapy

The development of formulation approaches to coadminister lopinavir and ritonavir antiretroviral drugs to children is necessary to ensure optimal treatment of human immunodeficiency virus (HIV) infection. It was previously shown that milk-based lipid formulations show promise as vehicles to deliver antimalarial drugs by enhancing their solubilization during the digestion of the milk lipids under intestinal conditions. In this study, we investigate the role of digestion of milk and infant formula on the solubilization behavior of lopinavir and ritonavir to understand the fate of drugs in the gastrointestinal (GI) tract after oral administration. Small angle X-ray scattering (SAXS) was used to probe the presence of crystalline drugs in suspension during digestion. In particular, the impact of one drug on the solubilization of the other was elucidated to reveal potential drug–drug interactions in a drug combination therapy. Our results showed that lopinavir and ritonavir affected the solubilization of each other during digestion in lipid-based formulations. While addition of ritonavir to lopinavir improved the overall solubilization of lopinavir, the impact of lopinavir was to reduce ritonavir solubilization as digestion progressed. These findings highlight the importance of assessing the solubilization of individual drugs in a combined matrix in order to dictate the state of drugs available for subsequent absorption and metabolism. Enhancement in the solubilization of lopinavir and ritonavir in a drug combination setting in vitro also supported the potential for food effects on drug exposure

Formation of Highly Organized Nanostructures during the Digestion of Milk

Nature’s own emulsion, milk, consists of nutrients such as proteins, vitamins, salts, and milk fat with primarily triglycerides. The digestion of milk fats is the key to the survival of mammal species, yet it is surprising how little we understand this process. The lipase-catalyzed hydrolysis of dietary fats into fatty acids and monoglyceride is essential for efficient absorption of the fat by the enterocytes. Here we report the discovery of highly ordered geometric nanostructures during the digestion of dairy milk. Transitions from normal emulsion through a variety of differently ordered nanostructures were observed using time-resolved small-angle X-ray scattering on a high-intensity synchrotron source and visualized by cryogenic transmission electron microscopy. Water and hydrophilic molecules are transferred into the lipid phase of the milk particle, turning the lipid core gradually into a more hydrophilic environment. The formation of highly ordered lipid particles with substantial internal surface area, particularly in low-bile conditions, may indicate a compensating mechanism for maintenance of lipid absorption under compromised lipolysis conditions

The Curious Case of the OZ439 Mesylate Salt: An Amphiphilic Antimalarial Drug with Diverse Solution and Solid State Structures

Efforts to develop orally administered drugs tend to place an exceptional focus on aqueous solubility as this is an essential criterion for their absorption in the gastrointestinal tract. In this work we examine the solid state behavior and solubility of OZ439, a promising single-dose cure for malaria being developed as the highly water-soluble mesylate salt. The aqueous phase behavior of the OZ439 mesylate salt was determined using a combination of small angle neutron and X-ray scattering (SANS and SAXS, respectively). It was found that this salt has low solubility at low concentrations with the drug largely precipitated in free base aggregates. However, with increasing concentration these crystalline aggregates were observed to dissociate into cationic micelles and lamellar phases, effectively increasing the dissolved drug concentration. It was also found that the dissolved OZ439 spontaneously precipitated in the presence of biologically relevant anions, which we attribute to the high lattice energies of most of the salt forms of the drug. These findings show that aqueous solubility is not always what it seems in the context of amphiphilic drug molecules and highlights that its use as the principal metric in selecting drug candidates for development can be perilous

Serendipity and Design in the Generation of New Coordination Polymers: An Extensive Series of Highly Symmetrical Guanidinium-Templated, Carbonate-Based Networks with the Sodalite Topology

The serendipitous discovery of a 3D [Cu(CO3)22-]n network with the topology of the 4264 sodalite net in [Cu6(CO3)12(CH6N3)8]·K4·8H2O paved the way for the deliberate engineering of an extensive series of structurally related guanidinium-templated metal carbonates of composition [M6(CO3)12(CH6N3)8]Na3[N(CH3)4]·xH2O, where the divalent metal M in the framework may be Mg, Mn, Fe, Co, Ni, Cu, Zn, or Cd. A closely related crystalline material with a [Ca(CO3)22-]n sodalite-like framework, but containing K+ rather than Na+, of composition [Ca6(CO3)12(CH6N3)8]K3[N(CH3)4]·3H2O was also isolated. All of these compounds were obtained under the simplest possible conditions from aqueous solution at room temperature, and their structures were determined by single-crystal X-ray diffraction. Pairs of guanidinium cations are associated with the hexagonal windows of the sodalite cages, alkali-metal cations are associated with their square windows, and N(CH3)4+ ions are located at their centers. Structures fall into two classes depending on the metal, MII, in the framework. One type, the BC type (Im3̄m), comprising the compounds for which M2+ = Ca2+, Mn2+, Cu2+, and Cd2+, has a body-centered cubic unit cell, while the second type, the FC type (Fd3̄c), for which M2+ = Mg2+, Fe2+, Co2+, Ni2+, and Zn2+, has a face-centered cubic unit cell with edges on the order of twice those of the BC structural type. The metal M in the BC structures has four close carbonate oxygen donors and four other more distant ones, while M in the FC structures has an octahedral environment consisting of two bidentate chelating carbonate ligands and two cis monodentate carbonate ligands

Serendipity and Design in the Generation of New Coordination Polymers: An Extensive Series of Highly Symmetrical Guanidinium-Templated, Carbonate-Based Networks with the Sodalite Topology

The serendipitous discovery of a 3D [Cu(CO3)22-]n network with the topology of the 4264 sodalite net in [Cu6(CO3)12(CH6N3)8]·K4·8H2O paved the way for the deliberate engineering of an extensive series of structurally related guanidinium-templated metal carbonates of composition [M6(CO3)12(CH6N3)8]Na3[N(CH3)4]·xH2O, where the divalent metal M in the framework may be Mg, Mn, Fe, Co, Ni, Cu, Zn, or Cd. A closely related crystalline material with a [Ca(CO3)22-]n sodalite-like framework, but containing K+ rather than Na+, of composition [Ca6(CO3)12(CH6N3)8]K3[N(CH3)4]·3H2O was also isolated. All of these compounds were obtained under the simplest possible conditions from aqueous solution at room temperature, and their structures were determined by single-crystal X-ray diffraction. Pairs of guanidinium cations are associated with the hexagonal windows of the sodalite cages, alkali-metal cations are associated with their square windows, and N(CH3)4+ ions are located at their centers. Structures fall into two classes depending on the metal, MII, in the framework. One type, the BC type (Im3̄m), comprising the compounds for which M2+ = Ca2+, Mn2+, Cu2+, and Cd2+, has a body-centered cubic unit cell, while the second type, the FC type (Fd3̄c), for which M2+ = Mg2+, Fe2+, Co2+, Ni2+, and Zn2+, has a face-centered cubic unit cell with edges on the order of twice those of the BC structural type. The metal M in the BC structures has four close carbonate oxygen donors and four other more distant ones, while M in the FC structures has an octahedral environment consisting of two bidentate chelating carbonate ligands and two cis monodentate carbonate ligands

Nature’s building blocks: Understanding the nanostructure and mechanical properties of collagen in biomaterials

Collagen is one of nature’s building blocks. It is the main structural component of skin, pericardium, cartilage, surgical scaffolds and many other tissues. These biomaterials play an important role in the medical industry. Collagen scaffolds are routinely used for tissue engineering and wound healing applications. Heart valves can be percutaneously replaced using bioengineered leaflets from bovine pericardium tissue. The hierarchical structure of collagen imparts strength and elasticity, both of which are functionally and aesthetically important. The architecture of collagen in these materials and how it changes under tension or compression is not fully understood. Synchrotron-based small angle X-ray scattering (SAXS) has been used to investigate the complex structure of collagen and its biomechanical response to tension and compression in pericardium, cartilage and tissue engineered scaffolds. In situ mechanical tests were done on the SAXS beamline at the Australian Synchrotron with a custom built rig capable of applying both tension and compression in situ. Collagen scaffolds were exposed to increasing strain. Results show that the the collagen fibrils’ structural response to strain depended on their initial orientation direction (Figure 1). SAXS of neonatal and adult pericardium uncovered significant differences with neonatal pericardium having a higher modulus of elasticity because of more aligned collagen fibrils than adult pericardium (Figure 2). This research advances our fundamental understanding of the structural mechanics of collagen and collagen based materials. By understanding collagen’s hierarchical structure and its biomechanical response in tissue engineered scaffolds and pericardium we gain valuable insight into how we can optimize their performance. For example, understanding the directional structural response of scaffold materials to strain influences how surgeons select and place the materials. Neonatal pericardium has been shown to be suitable for heart valve leaflet replacements owing to the higher alignment of collagen fibrils that provides the structural foundation for its superior strength

Serendipity and Design in the Generation of New Coordination Polymers: An Extensive Series of Highly Symmetrical Guanidinium-Templated, Carbonate-Based Networks with the Sodalite Topology

The serendipitous discovery of a 3D [Cu(CO3)22-]n network with the topology of the 4264 sodalite net in [Cu6(CO3)12(CH6N3)8]·K4·8H2O paved the way for the deliberate engineering of an extensive series of structurally related guanidinium-templated metal carbonates of composition [M6(CO3)12(CH6N3)8]Na3[N(CH3)4]·xH2O, where the divalent metal M in the framework may be Mg, Mn, Fe, Co, Ni, Cu, Zn, or Cd. A closely related crystalline material with a [Ca(CO3)22-]n sodalite-like framework, but containing K+ rather than Na+, of composition [Ca6(CO3)12(CH6N3)8]K3[N(CH3)4]·3H2O was also isolated. All of these compounds were obtained under the simplest possible conditions from aqueous solution at room temperature, and their structures were determined by single-crystal X-ray diffraction. Pairs of guanidinium cations are associated with the hexagonal windows of the sodalite cages, alkali-metal cations are associated with their square windows, and N(CH3)4+ ions are located at their centers. Structures fall into two classes depending on the metal, MII, in the framework. One type, the BC type (Im3̄m), comprising the compounds for which M2+ = Ca2+, Mn2+, Cu2+, and Cd2+, has a body-centered cubic unit cell, while the second type, the FC type (Fd3̄c), for which M2+ = Mg2+, Fe2+, Co2+, Ni2+, and Zn2+, has a face-centered cubic unit cell with edges on the order of twice those of the BC structural type. The metal M in the BC structures has four close carbonate oxygen donors and four other more distant ones, while M in the FC structures has an octahedral environment consisting of two bidentate chelating carbonate ligands and two cis monodentate carbonate ligands