Gd-DTPA-Dopamine-Bisphytanyl Amphiphile: Synthesis, Characterisation and Relaxation Parameters of the Nanoassemblies and Their Potential as MRI Contrast Agents.

Here, a new amphiphilic magnetic resonance imaging (MRI) contrast agent, a Gd(III)-chelated diethylenetriaminepentaacetic acid conjugated to two branched alkyl chains via a dopamine spacer, Gd-DTPA-dopamine-bisphytanyl (Gd-DTPA-Dop-Phy), which is readily capable of self-assembling into liposomal nanoassemblies upon dispersion in an aqueous solution, is reported. In vitro relaxivities of the dispersions were found to be much higher than Magnevist, a commercially available contrast agent, at 0.47 T but comparable at 9.40 T. Analysis of variable temperature (17)O NMR transverse relaxation measurements revealed the water exchange of the nanoassemblies to be faster than that previously reported for paramagnetic liposomes. Molecular reorientation dynamics were probed by (1)H NMRD profiles using a classical inner and outer sphere relaxation model and a Lipari-Szabo "model-free" approach. High payloads of Gd(III) ions in the liposomal nanoassemblies made solely from the Gd-DTPA-Dop-Phy amphiphiles, in combination with slow molecular reorientation and fast water exchange makes this novel amphiphile a suitable candidate to be investigated as an advanced MRI contrast agent.

Tracking the heat-triggered phase change of polydopamine-shelled, perfluorocarbon emulsion droplets into microbubbles using neutron scattering.

Perfluorocarbon emulsion droplets are hybrid colloidal materials with vast applications, ranging from imaging to drug delivery, due to their controllable phase transition into microbubbles via heat application or acoustic droplet vapourisation. The current work highlights the application of small- and ultra-small-angle neutron scattering (SANS and USANS), in combination with contrast variation techniques, in observing the in situ phase transition of polydopamine-shelled, perfluorocarbon (PDA/PFC) emulsion droplets with controlled polydispersity into microbubbles upon heating. We correlate these measurements with optical and transmission electron microscopy imaging, dynamic light scattering, and thermogravimetric analysis to characterise these emulsions, and observe their phase transition into microbubbles. Results show that the phase transition of PDA/PFC droplets with perfluorohexane (PFH), perfluoropentane (PFP), and PFH-PFP mixtures occur at temperatures that are around 30-40 °C higher than the boiling points of pure liquid PFCs, and this is influenced by the specific PFC compositions (perfluorohexane, perfluoropentane, and mixtures of these PFCs). Analysis and model fitting of neutron scattering data allowed us to monitor droplet size distributions at different temperatures, giving valuable insights into the transformation of these polydisperse, emulsion droplet systems.

Biomimetic Gemcitabine-Lipid Prodrug Nanoparticles for Pancreatic Cancer.

Gemcitabine (Gem) is a key drug for pancreatic cancer, yet limited by high systemic toxicity, low bioavailability and poor pharmacokinetic profiles. To overcome these limitations, Gem prodrug amphiphiles were synthesised with oleyl, linoleyl and phytanyl chains. Self-assembly and lyotropic mesophase behaviour of these amphiphiles were examined using polarised optical microscopy and Synchrotron SAXS (SSAXS). Gem-phytanyl was found to form liquid crystalline inverse cubic mesophase. This prodrug was combined with phospholipids and cholesterol to create biomimetic Gem-lipid prodrug nanoparticles (Gem-LPNP), verified by SSAXS and cryo-TEM to form liposomes. In vitro testing of the Gem-LPNP in several pancreatic cancer cell lines showed lower toxicity than Gem. However, in a cell line-derived pancreatic cancer mouse model Gem-LPNP displayed greater tumour growth inhibition than Gem using a fraction (<6 %) of the clinical dose and without any systemic toxicity. The easy production, improved efficacy and low toxicity of Gem-LPNP represents a promising new nanomedicine for pancreatic cancer.

PEGylation and surface functionalization of liposomes containing drug nanocrystals for cell-targeted delivery.

Liposomal formulations have important therapeutic applications in anti-cancer treatments but current formulations suffer from serious side effects, high dosage requirements and prolonged treatment. In this study, PEGylated azide-functionalized liposomes containing drug nanocrystals were investigated with the aim of increasing the drug payload and achieving functionalization for targeted delivery. Liposomes were characterized using cryogenic transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS), small and ultra-small angle neutron scattering (SANS/USANS) and small and wide angle X-ray scattering (SAXS/WAXS). Cryo-TEM experiments revealed the dimensions of the nanocrystal-loaded liposomes and the change of shape from spherical to elongated after the formation of nanocrystals. Results from SANS/USANS experiments confirmed the asymmetric particle shape. SAXS/WAXS experiments confirmed that the crystalline drug only occurred in freeze-thawed samples and correlated with a new unidentified polymorphic form of ciprofloxacin. Using a small molecule dye, dibenzocyclooctyne (DBCO)-cy5, specific conjugation between DBCO groups and surface azide groups on the liposomes was confirmed; this indicates the promise of this system for tumour-targeted delivery.

Structural evolution of photocrosslinked silk fibroin and silk fibroin-based hybrid hydrogels: A small angle and ultra-small angle scattering investigation.

Regenerated Bombyx mori silk fibroin (RSF) is a widely recognized protein for biomedical applications; however, its hierarchical gel structure is poorly understood. In this paper, the hierarchical structure of photocrosslinked RSF and RSF-based hybrid hydrogel systems: (i) RSF/Rec1-resilin and (ii) RSF/poly(N-vinylcaprolactam (PVCL) is reported for the first time using small-angle scattering (SAS) techniques. The structure of RSF in dilute to concentrated solution to fabricated hydrogels were characterized using small angle X-ray scattering (SAXS), small angle neutron scattering (SANS) and ultra-small angle neutron scattering (USANS) techniques. The RSF hydrogel exhibited three distinctive structural characteristics: (i) a Porod region in the length scale of 2 to 3nm due to hydrophobic domains (containing ß-sheets) which exhibits sharp interfaces with the amorphous matrix of the hydrogel and the solvent, (ii) a Guinier region in the length scale of 4 to 20nm due to hydrophilic domains (containing turns and random coil), and (iii) a Porod-like region in the length scale of few micrometers due to water pores/channels exhibiting fractal-like characteristics. Addition of Rec1-resilin or PVCL to RSF and subsequent crosslinking systematically increased the nanoscale size of hydrophobic and hydrophilic domains, whereas decreased the homogeneity of pore size distribution in the microscale. The presented results have implications on the fundamental understanding of the structure-property relationship of RSF-based hydrogels.