LS-4

Alzheimer's Disease (AD) is the most common neurodegenerative disease, and efficient therapeutic and early diagnostic agents for AD are still lacking. Herein, we report the development of a novel amphiphilic compound, LS-4, generated by linking a hydrophobic amyloid-binding distyrylbenzene fragment with a hydrophilic triazamacrocycle, which dramatically increases the binding affinity toward various amyloid β (Aβ) peptide aggregates, especially for soluble Aβ oligomers. Moreover, upon the administration of LS-4 to 5xFAD mice, fluorescence imaging of LS-4-treated brain sections reveals that LS-4 can penetrate the blood-brain barrier and bind to the Aβ oligomers in vivo. In addition, the treatment of 5xFAD mice with LS-4 reduces the amount of both amyloid plaques and associated phosphorylated tau aggregates vs the vehicle-treated 5xFAD mice, while microglia activation is also reduced. Molecular dynamics simulations corroborate the observation that introducing a hydrophilic moiety into the molecular structure of LS-4 can enhance the electrostatic interactions with the polar residues of the Aβ species. Finally, exploiting the Cu²⁺-chelating property of the triazamacrocycle, we performed a series of imaging and biodistribution studies that show the ⁶⁴Cu-LS-4 complex binds to the amyloid plaques and can accumulate to a significantly larger extent in the 5xFAD mouse brains vs the wild-type controls. Overall, these results illustrate that the novel strategy, to employ an amphiphilic molecule containing a hydrophilic moiety attached to a hydrophobic amyloid-binding fragment, can increase the binding affinity for both soluble and insoluble Aβ aggregates and can thus be used to detect and regulate various Aβ species in AD.

The fractionated coconut oil based Solid Lipid Nanoparticles (SLNs) of Acyclovir (ACV) were fabricated in two batches by using Glyceryl mono stearate (GMS) and Lipoid S75 (Fat free soybean phospholipids with 70% phosphatidylcholine-Lipoid GmbH, Germany). The research was focused on developing ACV-SLN by using high pressure hot-homogenization technique. The ingredients were used in different concentrations and ratios to identify the best formulation design.

The GMS with Fractionated coconut oil and Lipoid S75 with Fractionated coconut oil were used in various concentrations in formulation design to assess the impact on the fabrication and evaluation of SLNs. The SLNs were subjected to various characterization techniques such as XRD (X-Ray Diffraction), FTIR (Fourier transform infrared study), master sizer analysis and zeta potential. The mean particle size was determined by master sizer and zeta sizer. Transmission Electron Microscopy (TEM) was used as a tool to analyze the morphology and other features. The zeta potential and drug Entrapment Efficiency (EE%) were also determined. The drug release time profile was studied in vitro study with the utilization of dialysis membrane technique as well as by wistar rat skin. The most recent patents related to the current research topic were also discussed.

The Zeta potential of the best formulation from GMS batch GNE5 was found to be -2.62mV as the preparation was very viscous with low zeta potential. The better results of Lipoid S75 batch LS4 were found to be 23.23mV which was within the recommended range. The formulations prepared with Lipoid S75, LS4 showed narrow distribution size of 53.46nm and the uniformity was found to be 14.1. The formulation LS4 demonstrated the lowest distribution with of 6.8, 14.5, 139.1nm respectively amongst all the formulations.

SLN dispersions exhibited the average size in nano range. SLNs with small particle size found to have predetermined encapsulation efficiency and relatively high loading capacity and predetermined in vitro drugrelease profile. The lipoid S and Pluronic F68 nanoparticles are found to be superior to Conventional GMSand tween 80 nanoparticles in terms of particles size, stability and zetapotential.