The concept that extracellular vesicles (EVs) from the diet can be absorbed by the intestinal tract of the consuming organism, be bioavailable in various organs, and in-turn exert phenotypic changes is highly debatable. Here, we isolate EVs from both raw and commercial bovine milk and characterize them by electron microscopy, nanoparticle tracking analysis, western blotting, quantitative proteomics and small RNA sequencing analysis. Orally administered bovine milk-derived EVs survive the harsh degrading conditions of the gut, in mice, and is subsequently detected in multiple organs. Milk-derived EVs orally administered to mice implanted with colorectal and breast cancer cells reduce the primary tumor burden. Intriguingly, despite the reduction in primary tumor growth, milk-derived EVs accelerate metastasis in breast and pancreatic cancer mouse models. Proteomic and biochemical analysis reveal the induction of senescence and epithelial-to-mesenchymal transition in cancer cells upon treatment with milk-derived EVs. Timing of EV administration is critical as oral administration after resection of the primary tumor reverses the pro-metastatic effects of milk-derived EVs in breast cancer models. Taken together, our study provides context-based and opposing roles of milk-derived EVs as metastasis inducers and suppressors.

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neurodegenerative diseases (Alzheimer's, parkinson's etc.) causes brain cell damage leading to dementia. the major restriction remains in delivering drug to the central nervous system is blood brain barrier (BBB). the aim of this study was to develop a liposomal drug delivery system of Aphanamixis polystachya leaf extract for the treatment of neurodegenerative diseases such as Alzheimer's and parkinson's disease. in this study Gc-MS analysis is used to determine major constituents of Aphanamixis polystachya leaf extract. Liposomal batches of Aphanamixis polystachya leaf extract was prepared using design of experiment (Doe) and characterized using Malvern zetasizer, transmission electron microscopy (teM), and ft-iR. Stability study of blank and leaf extract loaded liposome were performed in gastric media. In-vivo neurobehavioral and anti-inflammatory studies were performed on mice and rat model respectively. Gc-MS data showed that major constituents of Aphanamixis polystachya leaf extract are 2-Pentanone, different acids (Octadec-9-enoic acid, 5-Hydroxypipeloic acid etc.), and Beta-elemene etc. Malvern Zetasizer and teM data showed that liposome batches of Aphanamixis polystachya leaf extract were in the range of 120-180 nm. Interactions between process parameters and material attributes found to have more impact on the average particle size and polydispersity of liposome batches compared to the impact of each parameter in isolation. Stability studies data suggest that blank and leaf extract loaded liposomes were stable at gastric conditions after 4 hours. In-vivo neurobehavioural study data indicated that significant improvement in the memory function, locomotor activity and ambulatory performance of dementia induced mice was observed for the liposomal batches compared to merely A. polystachya leaf extract. One of the most researched areas in medical science is neuropharmacology. About 1.5 billion people worldwide are suffering from central nervous system diseases and nearly half of adults above 70 years old are expected to develop neurodegenerative diseases such as Alzheimer's and Parkinson's 1. Dementia is a degenerative CNS condition that affects intellectual abilities and memory. Alzheimer's, Huntington's, and Parkinson's, which are neurodegenerative diseases, can cause damage to different sets of brain cells leading to dementia 2-4. Therefore, degenerative conditions, brain infections and stroke do alter the blood-brain barrier (BBB) causing foreign molecules to travers BBB and induce inflammation. However, altered BBB could be utilized as a mean for drug delivery into the brain. Currently, most therapies are symptomatic 5 , which make room for improvement in drug delivery system and potential discovery of new molecules. At present many CNS drugs such as tacrine, rivastigmine, donepezil, are cholinesterase inhibitor are used for the treatment of Alzheimer's disease. Their main restriction, however, remains in the proper delivery to target region due to the BBB 6-8 .

BackgroundNanotechnology can offer the advantages of increasing solubility and bioavailability of delivering drugs like Furosemide. The aim of the current study is to investigate the in vitro and in vivo performance of furosemide nanosuspensions.MethodsFurosemide nanosuspensions were prepared by antisolvent precipitation method using full factorial experimental design. Four factors were employed namely; Stirring time, Injection rate, antisolvent: solvent ratio & stabilizer: drug ratio (at two levels = high & low). The in vitro dissolution experiments were conducted to compare the representative formulation with raw drug powder. The bioavailability of nanosuspension was, also, evaluated in mice as an animal model.ResultsSolid state characterization (PXRD, DSC and FESEM) did show physical changes during preparation and optimization of the furosemide nanosuspensions. Individual material attributes showed more significant impact on the average particle size of the nanocrystals compared to process parameters. Two-way interactions between material attributes and process parameters significantly affected nanosuspension particle size distribution. Dissolution rate of furosemide nanosuspemsion was significantly higher than that observed for raw furosemide powder. The in vivo pharmacokinetics parameters of nanosuspension in comparison to pure drug showed significant increase in Cmax and AUC(0-t), about 233% and 266%, respectively. The oral bioavailability of furosemide from nanosuspension was about 2.3 fold higher as compared with the bioavailability from pure drug.ConclusionsFurosemide nanosuspensions prepared using antisolvent precipitation method enhanced the dissolution rate and oral bioavailability compared to raw furosemide powder.

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