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Specific, efficient and targeted delivery of siRNAs is the major concern for their in vivo administrations. Also, anatomical barriers, drug stability and availability, immunoreactivity and existence of various delivery routes, different genetic backgrounds are major clinical challenges. However, successful administration of siRNA-based drugs is expected during foreseeable features. But, their systemic applications will depend on strong targeted drug delivery strategies.

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Abstract1,2-Distigmasterylhemisuccinoyl-sn-glycero-3-phosphocholine (DSHemsPC) is a new lipid in which two molecules of stigmasterol (an inexpensive plant sterol) are covalently linked via a succinic acid to glycerophosphocholine. Since amphotericin B (AmB) interacts with sterols, we postulated that DSHemsPC could be used in AmB liposome formulations. Thirty-two DSHemsPC-AmB formulations were prepared using various mole ratios of DSHemsPC, phosphatidylcholine and phosphatidylglycerol at different pH. Most formulations had physical properties similar to AmBisome™: a particle diameter of about 100 nm, a monomodal distribution and a negative zeta potential. The red blood cell potassium release (RBCPR) IC50s for formulations spanned a range, with some being comparable to or greater than the IC50 observed using AmBisome™. A number of formulations had superior in vitro antifungal activity compared to AmBisome™. against all of the tested pathogenic yeasts and molds. The IC50s of formulations against L. major promastigotes and amastigotes for certain formulations were comparable with AmBisome™ and Fungizone™. Most formulations had maximum tolerated intravenous doses (MTD) of less than 10 mg/kg. However the formulation consisting of DSHemsPC/DMPC/DMPG/ AmB mole ratio 1.25/5.0/1.5/1.0 (prepared at pH 5.5) had excellent colloidal properties, a high IC50 for RBCPR, antifungal and antileishmanial activity similar to AmBisome™ and an MTD of 60 mg/kg. The characteristics of this DSHemsPC/DMPC/DMPG/AmB formulation make it suitable for further investigation to treat AmB-responsive pathogens.

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1,2-Distigmasterylhemisuccinoyl-sn-glycero-3-phosphocholine (DSHemsPC) is a new lipid in which two molecules of stigmasterol (an inexpensive plant sterol) are covalently linked via a succinic acid to glycerophosphocholine. Our previous study revealed that liposome (Lip)-intercalated amphotericin B (AMB) prepared from DSHemsPC (DSHemsPC-AMB-Lip) possesses excellent colloidal properties and in vitro antifungal and antileishmanial activities similar to those of the liposomal AMB preparation AmBisome. The aim of this study was to determine the biodistribution and evaluate the antileishmanial effects of DSHemsPC-AMB-Lip in Leishmania majorinfected BALB/c mice. The serum profile and tissue concentrations of AMB were similar in DSHemsPC-AMB-Lip-and AmBisome-treated mice after intravenous (i.v.) injection. Multiple i.v. doses of the micellar formulation of AMB (Fungizone; 1 mg/kg of body weight), DSHemsPC-AMB-Lip (5 mg/kg), and AmBisome (5 mg/kg) were used in L. major-infected BALB/c mouse models of early and established lesions. In a model of the early lesions of cutaneous leishmaniasis (CL), the results indicated that the level of footpad inflammation was significantly (P Ͻ 0.001) lower in mice treated with DSHemsPC-AMB-Lip and AmBisome than mice treated with empty liposomes or 5% dextrose. The splenic and footpad parasite load was also significantly (P Ͻ 0.001) lower in these groups of mice than in control mice that received 5% DW or free liposome. The in vivo activity of DSHemsPC-AMB-Lip was comparable to that of AmBisome, and both provided improved results compared to those achieved with Fungizone at the designated doses. The results suggest that systemic DSHemsPC-AMB-Lip administration may be useful for the treatment of leishmaniasis, and because it costs less to produce DSHemsPC-AMB-Lip than AmBisome, DSHemsPC-AMB-Lip merits further investigation.

Abstract:Fifteen compounds related to ameltolide with sodium channel inhibitory activity were subjected to a molecular docking study. The chemical structures of all compounds were built using the program HyperChem and conformational studies were performed with a semiempirical method followed by the PM3 method. A docking study was performed using the program AutoDock on all the compounds. To confirm the binding mode of inhibitors, molecular dynamics simulations were performed using GROMACS 4.5.5, based upon the docked conformation of ameltolide. The docking analyses indicated that these compounds interacted mainly with residues II-S6 and III-S6 of NaV1.2 by making hydrogen bonds and ( π − π) interactions with domains I, III, and IV in the channel's inner pore. Our docking study reveals that amide linker plays a major role in the drug-receptor interaction. The results of molecular dynamic simulations confirmed the binding mode of ligands, the accuracy of docking, and the reliability of active conformations obtained by AutoDock.

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