Synthesis, Characterizations, and Use of O-Stearoyl Mannose Ligand-Engineered Lipid Nanoarchitectonics for Alveolar Macrophage Targeting.

The main challenging aspect in the management of tuberculosis (TB) diseases is effective alveolar macrophages targeting. Macrophage mannose receptor plays a predominant role in stimulating immune systems by TB pathogen. Our earlier in silico computational studies revealed that O-stearoyl mannose (OSM) possesses a higher affinity with macrophage mannose receptors. Therefore, keeping this in view, we developed OSM with the association of stearic acid and d-mannose as initial reactants by the esterification process. Preliminary confirmation of reaction was assessed with thin-layer chromatography experimentation, whereas further confirmation followed by in vitro characterization with several analytical experimental tools such as fourier transform near-infrared, differential scanning calorimetry, and electrospray ionization-assisted mass spectrometry confirms the formation of the OSM. This synthesized and well-characterized OSM as a ligand was further incubated with surface-engineered lipid nanoarchitectonics to achieve OSM ligand-engineered lipid nanoarchitectonics and earlier explored for its safety study through hemolysis assay and potential in vitro triggering efficiency in human alveolar macrophages (THP-1 cells) to validate its active targeting efficiency. Graphical Abstract [Figure: see text].

Merged experimental guided computational strategy toward tuberculosis treatment mediated by alveolar macrophages mannose receptor.

Macrophage mannose receptor (MMR) is a C-type lectin that regulates the phagocytosis and phagocytosis-lysosome (P-L) fusion in tuberculosis. Mannose-capped lipoarabinomannan, a lipoglycan present at the surface of Mycobacterium tuberculosis, is an important factor in phagocyte attachment and internalization that is specific for MMR. Based on this idea, herein we have designed our experiment to understand the better site-specific delivery against tuberculosis. An experimental outcome was used as a basis to revisit the reverse experimental strategy for tuberculosis management. Stearic mannose was prepared from stearic acid incubation with the D-mannose. Interestingly, stearic mannose explained its internalization via stimulating actin-mediated phagocytic pathway of MMR experimentally. Following, an in silico strategy towards hypothetical designing of various mannose-stearyl conjugates (SBKK1-7) against tuberculosis, as binding promoter of MMR (PDB: 1EGI), was carried out using molecular docking and dynamics approaches. Overall, SPKK-5 viz. ortho stearic mannose showed a higher binding affinity with notable H-bonding and hydrophobic interactions. Pharmacokinetic and toxicity examinations illustrated an ideal range of descriptors values for apex screened compounds. Molecular dynamics simulations have confirmed its significant intactness with the MMR. Ultimately, the whole effort led to the identification of promising hit (SBKK-5), which positively correlates with the experimental work and furthermore need to explore its novel drug delivery systems with improved anti-tubercular therapy.Communicated by Ramaswamy H. Sarma.

Long Acting Ionically Paired Embonate Based Nanocrystals of Donepezil for the Treatment of Alzheimer's Disease: a Proof of Concept Study.

PURPOSE: The aim of the present study was to prepare a patient friendly long acting donepezil (D) nanocrystals (NCs) formulation, with a high payload for i.m administration. As the native D hydrochloride salt has high aqueous solubility it is necessary to increase its hydrophobicity prior to the NCs formation. METHODS: D was ionically paired with embonic acid (E) in aqueous media and was successfully characterized using techniques like DSC, PXRD, FT-IR, NMR etc. Later, we converted the bulk ion pair into NCs using high pressure homogenization technique to study further in-vitro and in-vivo. RESULTS: The bulk ion pair has a drug content of 66% w/w and an 11,000 reduced solubility in comparison to native D hydrochloride. Also, its crystalline nature was confirmed by DSC and PXRD. The possible interaction sites responsible for the ion pair formation were identified though NMR. The prepared NCs has mean particle size 677.5 ± 72.5 nm and PDI 0.152 ± 0.061. In-vitro release showed a slow dissolution of NCs. Further, excellent bio compatibility of NCs were demonstrated in 3T3 cells. Following i.m administration of single dose of NCs, the D plasma level was found to be detectable up to 18 days. In vivo pharmacodynamic studies revealed that the single dose NCs i.m injection improved spatial memory learning and retention in ICV STZ model. CONCLUSION: Our results suggest that the developed formulation has a potential to replace the current daily dosing regimen to a less frequent dosing schedule. Graphical Abstract Improved pharmacokinetic and pharmacodynamic profile after administration of single dose donpezil embonate nanocrystals in Rats.