Background: The purpose of our study was to find a novel targeted imaging and drug delivery vehicle for inflammatory bowel disease (IBD). IBD is a common and troublesome disease which still lacks effective therapy and imaging options. As an attempt to improve the disease treatment, we tested αMSH for the targeting of nanoliposomes to IBD sites. αMSH, an endogenous tridecapeptide, binds to the melanocortin-1 receptor (MC1-R) and has antiinflammatory and immunomodulating effects. MC1-R are found on macrophages, neutrophils and the renal tubule system. We have formulated and tested a liposomal nanoparticle involving αMSH in order to achieve a specific targeting to the inflamed intestines. Methods: NDP-αMSH peptide conjugated to Alexa Fluor™ 680 was linked to the liposomal membrane via N-Succinyl PE and additionally loaded into the lumen of the liposomes. Liposomes without the αMSH-conjugate and free NDP- αMSH were used as a control. The liposomes were also loaded with ICG to track them. The liposomes were tested in DSS treated mice, which had received DSS via drinking order to develop a model IBD. Inflammation severity was assessed by the Disease Activity Index (DAI) score and ex vivo histological CD68 staining of samples taken from different parts of the intestine. The liposome targeting was analyzed by analyzing the ICG and ALEXA 680 fluorescence in the intestine compared to the biodistribution. Results: NPD-αMSH was successful labelled with Alexa and retained its biological activity. Liposomes located to expected destinations in the inflamed bowel regions and in the kidneys, where MC1-R are abundant. In vivo liposome targeting correlated with the macrophage concentration at the site of the inflammation supporting the active targeting of the liposomes through αMSH. The liposomal αMSH was well tolerated by animals. Conclusions: This study opens up the possibility to further develop an αMSH targeted theranostic delivery towards clinically relevant different applications in IBD inflammation but also opens possibilities in other inflammations like lung inflammation in Covid 19.
Background: Nanoparticle imaging and the imaging of the release of the loaded material from a nanoparticle system have attracted great attention in recent years. If the release of loaded molecules from delivery vehicles could be monitored reliably in vivo, it would speed up the development of drug delivery systems remarkably. Methods: Here we test a system that uses indocyanine green (ICG) as a fluorescent agent for studying release kinetics in vitro and in vivo of a lipid iron nanoparticle delivery system. The ICG spectral properties like its concentration, sensitivity and its fluctuations of absorption and emission wavelengths of the fluorescence can be utilized for gathering information about the change of the ICG surroundings. Results: We have found that the absorption, fluorescence, and photoacoustic spectra of the ICG in lipid iron nanoparticles differ from the spectra of ICG in the pure water and in plasma. We followed the ICG containing liposomal nanoparticle uptake into the squamous carcinoma cells (SCC) under a fluorescence microscopy and into SCC tumor in the nude mice orthotopic xenografts model under a surgical microscope. Conclusion: Absorption and emission properties of ICG in different solvent environment, like in plasma and human serum albumin, differ from those in aqueous solution. Photoacoustic spectral imaging confirmed a peak shift towards longer wavelengths and an intensity increase of ICG when bound to lipid. The SCC cells showed that the ICG containing liposomes bind to cell surface but are not internalized in the SCC-9 cells in 30 minutes’ incubation. We also showed here that ICG containing liposomal nanoparticles can be traced under a surgical camera in vivo in orthotopic SCC xenografts in mice.
Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gastrointestinal tract, resulting in severe symptoms. At the moment, the goal of medical treatments is to reduce inflammation. IBD is treated with systemic anti-inflammatory compounds, but they have serious side effects. The treatment that is most efficient and causes the fewest side effects would be the delivery of the drugs on the disease site. This study aimed to investigate the suitability of sphingomyelin (SM) containing liposomes to specifically target areas of inflammation in dextran sulfate sodium-induced murine colitis. Sphingomyelin is a substrate to the sphingomyelinase enzyme, which is only present outside cells in cell stress, like inflammation. When sphingomyelin consisting of liposomes is predisposed to the enzyme, it causes the weakening of the membrane structure. We demonstrated that SM-liposomes are efficiently taken up in intestinal macrophages, indicating their delivery potential. Furthermore, our studies showed that sphingomyelinase activity and release are increased in a dextran sulfate sodium-induced IBD mouse model. The enzyme appearance in IBD disease was also traced in intestine samples of the dextran sulfate sodium-treated mice and human tissue samples. The results from the IBD diseased animals, treated with fluorescently labeled SM-liposomes, demonstrated that the liposomes were taken up preferentially in the inflamed colon. This uptake efficiency correlated with sphingomyelinase activity.
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