Simulation of Calcium Phosphate Pre-Nucleation Clusters in Aqueous Solution: Association Beyond Ion Pairing

© 2019 American Chemical Society. Classical molecular dynamics simulations and free energy methods have been used to obtain a better understanding of the molecular processes occurring prior to the first nucleation event for calcium phosphate biominerals. The association constants for the formation of negatively charged complexes containing calcium and phosphate ions in aqueous solution have been computed, and these results suggest that the previously proposed calcium phosphate building unit, [Ca(HPO4)3]4-, should only be present in small amounts under normal experimental conditions. However, the presence of an activation barrier for the removal of an HPO42- ion from this complex indicates that this species could be kinetically trapped. Aggregation pathways involving CaHPO4, [Ca(HPO4)2]2-, and [Ca(HPO4)3]4- complexes have been explored with the finding that dimerization is favorable up to a Ca/HPO4 ratio of 1:2

Controlling the melting transition of semi-crystalline self-assembled block copolymer aggregates: controlling release rates of ibuprofen

Bicontinuous nanospheres and multi-lamellar micelles were self-assembled from poly[ethylene oxide]-block-(poly[octadecyl methacrylate]-random-poly[docosyl methacrylate]), (PEO-b-[PODMA-co-PDSMA]) where PEO is the hydrophilic block (25 wt%) and PODMA/PDSMA is the semi-crystalline hydrophobic block (75 wt%) that gives a thermoresponsive component to the self-assembled aggregates. By varying the relative molar proportion of DSMA to ODMA (from 0 : 1 to 1 : 0) in the synthesis of the copolymers by atom transfer radical polymerisation, the melting transition Tm of the hydrophobic block could be varied from 21.5 to 41.1 °C in the solid state. When self-assembled in aqueous dispersions the Tm range was 23.4 to 41.3 °C, closely matching that of the solid samples. Preliminary analysis of the rate of release of ibuprofen from three of the block copolymer aggregates demonstrated that the rate of release was correlated with the degree of crystallinity of the hydrophobic block and that increasing temperature causes melting and a significantly enhanced release rate

One Peptide for Them All: Gold Nanoparticles of Different Sizes Are Stabilized by a Common Peptide Amphiphile

The functionalization of gold nanoparticles (GNPs) with peptidic moieties can prevent their aggregation and facilitate their use for applications both in vitro and in vivo. To date, no peptide-based coating has been shown to stabilize GNPs larger than 30 nm in diameter; such particles are of interest for applications including vaccine development, drug delivery, and sensing. Here, GNPs with diameters of 20, 40, and 100 nm are functionalized with peptide amphiphiles. Using a combination of transmission electron microscopy, UV–vis spectroscopy, and dynamic light scattering, we show that GNPs up to 100 nm in size can be stabilized by these molecules. Moreover, we demonstrate that these peptide amphiphiles form curvature-dependent, ordered structures on the surface of the GNPs and that the GNPs remain disperse at high-salt concentrations and in the presence of competing thiol-containing molecules. These results represent the development of a peptide amphiphile-based coating system for GNPs which has the potential to be beneficial for a wide range of biological applications, in addition to image enhancement and catalysis.Supramolecular & Biomaterials Chemistr

The evolution of bicontinuous polymeric nanospheres in aqueous solution

Complex polymeric nanospheres in aqueous solution are desirable for their promising potential in encapsulation and templating applications. Understanding how they evolve in solution enables better control of the final structures. By unifying insights from cryoTEM and small angle X-ray scattering (SAXS), we present a mechanism for the development of bicontinuous polymeric nanospheres (BPNs) in aqueous solution from a semi-crystalline comb-like block copolymer that possesses temperature-responsive functionality. During the initial stages of water addition to THF solutions of the copolymer the aggregates are predominantly vesicles; but above a water content of 53% irregular aggregates of phase separated material appear, often microns in diameter and of indeterminate shape. We also observe a cononsolvency regime for the copolymer in THF–water mixtures from 22 to 36%. The structured large aggregates gradually decrease in size throughout dialysis, and the BPNs only appear upon cooling the fully aqueous dispersions from 35 °C to 5 °C. Thus, the final BPNs are ultimately the result of a reversible temperature-induced morphological transition

Anionic lipid nanoparticles preferentially deliver mRNA to the hepatic reticuloendothelial system

Lipid nanoparticles (LNPs) are the leading nonviral technologies for the delivery of exogenous RNA to target cells in vivo. As systemic delivery platforms, these technologies are exemplified by Onpattro, an approved LNP-based RNA interference therapy, administered intravenously and targeted to parenchymal liver cells. The discovery of systemically administered LNP technologies capable of preferential RNA delivery beyond hepatocytes has, however, proven more challenging. Here, preceded by comprehensive mechanistic understanding of in vivo nanoparticle biodistribution and bodily clearance, an LNP-based messenger RNA (mRNA) delivery platform is rationally designed to preferentially target the hepatic reticuloendothelial system (RES). Evaluated in embryonic zebrafish, validated in mice, and directly compared to LNP-mRNA systems based on the lipid composition of Onpattro, RES-targeted LNPs significantly enhance mRNA expression both globally within the liver and specifically within hepatic RES cell types. Hepatic RES targeting requires just a single lipid change within the formulation of Onpattro to switch LNP surface charge from neutral to anionic. This technology not only provides new opportunities to treat liver-specific and systemic diseases in which RES cell types play a key role but, more importantly, exemplifies that rational design of advanced RNA therapies must be preceded by a robust understanding of the dominant nano-biointeractions involved.Supramolecular & Biomaterials Chemistr

Crystallization by particle attachment in synthetic, biogenic, and geologic environments.

Field and laboratory observations show that crystals commonly form by the addition and attachment of particles that range from multi-ion complexes to fully formed nanoparticles. The particles involved in these nonclassical pathways to crystallization are diverse, in contrast to classical models that consider only the addition of monomeric chemical species. We review progress toward understanding crystal growth by particle-attachment processes and show that multiple pathways result from the interplay of free-energy landscapes and reaction dynamics. Much remains unknown about the fundamental aspects, particularly the relationships between solution structure, interfacial forces, and particle motion. Developing a predictive description that connects molecular details to ensemble behavior will require revisiting long-standing interpretations of crystal formation in synthetic systems, biominerals, and patterns of mineralization in natural environments

Intermolecular channels direct crystal orientation in mineralized collagen

The mineralized collagen fibril is the basic building block of bone, and is commonly pictured as a parallel array of ultrathin carbonated hydroxyapatite (HAp) platelets distributed throughout the collagen. This orientation is often attributed to an epitaxial relationship between the HAp and collagen molecules inside 2D voids within the fibril. Although recent studies have questioned this model, the structural relationship between the collagen matrix and HAp, and the mechanisms by which collagen directs mineralization remain unclear. Here, we use XRD to reveal that the voids in the collagen are in fact cylindrical pores with diameters of ~2 nm, while electron microscopy shows that the HAp crystals in bone are only uniaxially oriented with respect to the collagen. From in vitro mineralization studies with HAp, CaCO3 and γ-FeOOH we conclude that confinement within these pores, together with the anisotropic growth of HAp, dictates the orientation of HAp crystals within the collagen fibril