Differential Uptake of Murine and Human Exosomes by Normal and Inflamed Peripheral Tissues and Brain

Background: Exosomes function as an intercellular communication system conveying messages from donor to target cells in nearby or distant tissues. Many aspects of exosome trafficking remain unresolved, however. Here, we investigated uptake of ten radiolabeled murine or human exosomes of various cellular origins by the liver, kidney, spleen, and lung of male CD-1 mice. Methods: We radioactively labeled 10 exosomes from mouse or human cancerous or non-cancerous lines, injected them intravenously into male CD-1 mice, and studied their tissue uptake. We examined the ability of wheatgerm agglutinin (WGA), mannose-6 phosphate (M6P), and inflammation induced by lipopolysaccharide (LPS) to modulate uptake. We measured uptake rate using multiple-time regression analysis and used heat mapping and path analysis to correlate tissue and exosomal influences on uptake. Results: Except for the uptake of SCCVII exosomes by kidney, all exosomes were taken up by all tissues, although the uptake levels varied broadly among exosomes and tissues. The liver/serum uptake ratio for exosomes from primary human T-cells was the highest at 4,500 mL/g. Species of origin (mouse vs human) or source (cancerous vs noncancerous cells) did not influence tissue uptake. The uptake of some exosomes was altered by WGA and LPS but not by M6P, except for uptake inhibition of J774A.1 exosomes by liver, suggesting use of the M6P receptor. WGA or LPS treatments enhanced uptake of exosomes by brain and lung but inhibited uptake by liver and spleen. Response to LPS was not, however, predictive of response to WGA. No evidence for a universal binding site controlling exosome uptake was obtained. Applying path analysis and heat map analysis to the data, including our published results for brain, we found that exosome uptake patterns for lung and brain responded similarly to WGA or to LPS, whereas those for liver and spleen clustered together. In path analysis, the 10 exosomes clustered into distinct groups, suggesting that their bindings sites are similarly clustered. Conclusions: Uptake of exosomes by peripheral tissues is differentially regulated by both exosomes and target tissues and is dependent on the number and types of mutually interactive binding sites.

Liposome assisted drug delivery-A review

Liposomes, sphere-formed vesicles consisting of one or greater phospholipid bilayers, had been first described within the mid-60s. Among numerous gifted new drug delivery systems, liposomes signify an advanced generation to supply active molecules to the site of action, and right now, numerous formulations are in clinical use. The application of liposomes to help drug shipping has already had a chief impact on many biomedical regions. They have been proven to be beneficial for stabilizing pharmaceuticals, overcoming boundaries to cellular and tissue uptake, and improving biodistribution of compounds to goal sites In vivo. This permits powerful delivery of encapsulated compounds to goal sites even as minimizing systemic toxicity. Liposomes present as an attractive transport gadget due to their wide physicochemical and biophysical properties which allow smooth manipulation to cope with exclusive shipping concerns. In this review, we will talk the advances in liposome assisted drug shipping, biological challenges, and present day medical and experimental use of liposomes for biomedical applications. The translational limitations of liposomal technology may also be provided.

Glutathione-loaded non-ionic surfactant niosomes: A new approach to improve oral bioavailability and hepatoprotective efficacy of glutathione

A new formulation (niosomes) was prepared to enhance the bioavailability, hepatic tissue uptake, and hepatoprotective activity of glutathione (GSH). The GSH-loaded niosomes (nanoform, N-GSH) were formulated by the thin-film hydration technique using cholesterol/non-ionic surfactants (Span®40, Span®60, and Tween®80) at a componential ratio of 1:1 and 2:1. The hepatoprotective activity of N-GSH, GSH, and the standard silymarin against CCl4-induced liver damage and oxidative stress were tested on the rats’ model. The hepatic morphology and histopathological characters were also investigated. The tissue contents of N-GSH were analysed using a concurrently validated RP-HPLC method. The optimized niosomes, composed of glutathione (500 mg), cholesterol, and Span®60-Tween®80 at a molar ratio of 2:1 of cholesterol/non-ionic surfactant, displaying a particle size of 688.5 ± 14.52 nm, a zeta potential of −26.47 ± 0.158 mV, and encapsulation efficiency (EE) of 66 ± 2.8% was selected for in vivo testing. The levels of MDA, NO, SOD, NF-κB, IL-1β, and Bcl-2 were measured. The results demonstrated that hepatic tissue damage was ameliorated using N-GSH as confirmed by the morphological and histopathological examination compared to the CCl4 and control groups. The N-GSH significantly (p < 0.05) decreased the elevated levels of hepatic enzymes, oxidative parameters, and inflammatory mediators, as compared to silymarin and GSH. Also, N-GSH significantly (p < 0.05) increased GSH hepatocyte concentrations as compared to the control groups. The present study demonstrated that N-GSH remarkably improved glutathione oral bioavailability and hepatic tissue uptake, thereby introducing a new glutathione formulation to protect hepatic tissue from injury and restore its GSH contents.

Effect of metformin on 18F-fluorodeoxyglucose uptake and positron emission tomographic imaging

Metformin is widely used to treat diabetes, but induces changes in glucose uptake in both normal organs and tumors. Here, we review the effects of metformin on the uptake of 18F-fluorodeoxyglucose (18F-FDG) in tissues and tumors, and its influence on 18F-FDG positron emission tomographic imaging (18F-FDG PET), as well as the mechanisms involved. This is an important issue, because metformin has diverse effects on tissue uptake of 18F-FDG, and this can affect the quality and interpretation of PET images. Metformin increases glucose uptake in the gastrointestinal tract, cerebral white matter, and the kidney, while regions of the cerebrum associated with memory show decreased glucose uptake, and the myocardium shows no change. Hepatocellular carcinoma and breast cancer show increased glucose uptake after metformin administration, while thyroid cancer shows decreased uptake, and colon and pancreatic cancers show no change. A high-energy diet increases 18F-FDG uptake, but this effect is blocked by metformin. Withdrawal of metformin 48 h before PET image acquisition is widely recommended. However, based on our review of the literature, we propose that the differentiation of metformin discontinuation could be reasonable. But future clinical trials are still needed to support our viewpoint.

Enhanced intraperitoneal delivery of charged, aerosolized curcumin nanoparticles by electrostatic precipitation

Aims: To investigate the potential of curcumin-loaded polylactic-co-glycolic acid nanoparticles (CUR-PLGA-NPs), alone and with electrostatic precipitation, for improving tissue uptake during pressurized intraperitoneal aerosol chemotherapy (PIPAC). Methods: Positively and negatively charged CUR-PLGA-NPs were delivered as PIPAC into inverted bovine urinary bladders ex vivo. The experiment was repeated with the additional use of electrostatic precipitation pressurized intraperitoneal aerosol chemotherapy (electrostatic PIPAC). Results: Positively charged CUR-PLGA-NPs increased depth of tissue penetration by 81.5% and tissue concentration by 80%. Electrostatic precipitation further improved the uptake of positively charged CUR-PLGA-NPs by 41.8%. Conclusion: The combination of positive charge and electrostatic precipitation have significant potential to improve tissue uptake of nanoparticles during intraperitoneal chemotherapy.

Net release and uptake of xenometabolites across intestinal, hepatic, muscle, and renal tissue beds in healthy conscious pigs

Xenometabolites from microbe origins influence host health and disease, but absorption and tissue uptake of these metabolites remain speculative. Results herein are the first to demonstrate in vivo organ uptake and release of these metabolites. We used a conscious catheterized pig model to confirm gastrointestinal origins for several xenometabolites (e.g., indolic compounds, 4-hydroxyphenyllactic acid, dodecanendioic acid, and phenylacetylgycine). Liver and kidney were major sites for xenometabolite uptake, likely highlighting liver conjugation metabolism and renal excretion.

Recombinant Human Plasma Gelsolin Stimulates Phagocytosis while Diminishing Excessive Inflammatory Responses in Mice with Pseudomonas aeruginosa Sepsis

Plasma gelsolin (pGSN) is a highly conserved abundant circulating protein, characterized by diverse immunomodulatory activities including macrophage activation and the ability to neutralize pro-inflammatory molecules produced by the host and pathogen. Using a murine model of Gram-negative sepsis initiated by the peritoneal instillation of Pseudomonas aeruginosa Xen 5, we observed a decrease in the tissue uptake of IRDye®800CW 2-deoxyglucose, an indicator of inflammation, and a decrease in bacterial growth from ascitic fluid in mice treated with intravenous recombinant human plasma gelsolin (pGSN) compared to the control vehicle. Pretreatment of the murine macrophage line RAW264.7 with pGSN, followed by addition of Pseudomonas aeruginosa Xen 5, resulted in a dose-dependent increase in the proportion of macrophages with internalized bacteria. This increased uptake was less pronounced when cells were pretreated with pGSN and then centrifuged to remove unbound pGSN before addition of bacteria to macrophages. These observations suggest that recombinant plasma gelsolin can modulate the inflammatory response while at the same time augmenting host antibacterial activity.

SAT-417 Personalized Treatment Planning for Radioiodine Therapy of Graves’ Disease;The Collar Therapy Indicator(CoTI)

Introduction Since its introduction 80 years ago, the therapeutic I-131 dosage has usually been tailored to individual patient requirements based on the uptake of a tracer radio-iodine(RAI) dose. Estimated exposure has typically been extrapolated from the results of activity measurements at one or two time points, e.g., at 4 and 24 hours. We now know that treatment of hyperthyroid Graves disease with these methods lead to a 13–25% rate of failure to cure hyperthyroidism and a 46–80% rate of long-term hypothyroidism in cured patients. There is a need for a much more personalized approach to RAI dosing based on individual RAI tissue uptake, kinetics. This can be achieved only after including multiple data points during the evaluation of tissue uptake. The Collar Therapy Indicator (CoTI), a device placed in cloth collar around the neck resembling a turtle neck sweater collar with a connecting wire and recording box, has been shown in small feasibility studies to provide data regarding radioiodine exposure that correlates with conventional methods of measuring I-123 and I-131 uptakes after diagnostic dose administration and/or therapy for thyroid disorders Methods; We hypothesized that the device’s continuous measurement capability will permit more accurate estimates of radiation exposure to thyroid tissue than conventionally employed methods assessing fractional uptake at one or a few time points. It may also provide information about the extent of variability in the absorbed radiation dose among patients with hyperthyroidism. We performed a feasibility study in a patient with graves’ disease to see the difference between tradition methods of I-123 uptake and the CoTI; (1) We compared the conventional quantitative uptake-derived thyroid time activity curve (TAC) as well as the Area Under the Curve (AUC)(based on percent uptake at 6 hour and 24 hour time points) to that obtained using the CoTI.(2) We evaluated the uptake and clearance kinetics of diagnostic I-123 administered.(3) We also evaluated patient experience in using the CoTI device with a survey instrument. Results; The CoTI plotted TAC and AUC offered a different approach from the conventional methods of calculation (6 hr and 24 hr % uptake) of I-123 TAC and AUC. The patient reported no difficulty in using the device and the device itself was not inconvenient. Conclusions; The calculation of % uptake as well as rate of uptake within the thyroid by CoTI might help us, in achieving a more personalized approach to I-131 RAI dose calculation for treatment of Graves’ disease. The preliminary research findings that we have generated will help us investigate different aspects of RAI uptake within the thyroid and will hopefully lead to solutions, for some of the common issues and problems arising out of random dosing of RAI.