Copper (Cu)(II) ions, mainly an excess amount, play a negative role in the course of several diseases, like cancers, neurodegenerative diseases, and the so-called Wilson disease. On the contrary, Cu(II) ions are also capable of improving anticancer drug efficiency. For this reason, it is of great interest to study the interacting ability of Cu(II)− nanodrug and Cu(II)−nanocarrier complexes with cell membranes for their potential use as nanotherapeutics. In this study, the complex interaction between 1,4,7,10-tetraazacyclododecan-N,N′,N′′,N′′′-tetraacetic acid (DOTA)-functionalized poly(propyleneimine) (PPI) glycodendrimers and Cu(II) ions and/or neutral and anionic lipid membrane models using different liposomes is described. These interactions were investigated via dynamic light scattering (DLS), ζ-potential (ZP), electron paramagnetic resonance (EPR), fluorescence anisotropy, and cryogenic transmission electron microscopy (cryo-TEM). Structural and dynamic information about the PPI glycodendrimer and its Cu(II) complexes toward liposomes was obtained via EPR. At the binding site Cu−N 2 O 2 coordination prevails, while at the external interface, this coordination partially weakens due to competitive dendrimer−liposome interactions, with only small liposome structural perturbation. Fluorescence anisotropy was used to evaluate the membrane fluidity of both the hydrophobic and hydrophilic parts of the lipid bilayer, while DLS and ZP allowed us to determine the distribution profile of the nanoparticle (PPI glycodendrimer and liposomes) size and surface charge, respectively. From this multitechnique approach, it is deduced that DOTA-PPI glycodendrimers selectively extract Cu(II) ions from the bioenvironment, while these complexes interact with the liposome surface, preferentially with even more negatively charged liposomes. However, these complexes are not able to cross the cell membrane model and poorly perturb the membrane structure, showing their potential for biomedical use.

Ulcerative colitis is a chronic inflammatory bowel disease that strongly affects patient quality of life. Side effects of current therapies necessitate new treatment strategies that maximise the drug concentration at the site of inflammation, while minimizing systemic exposure. Capitalizing on the biocompatible and biodegradable structure of lipid mesophases, we present a temperature-triggered in situ forming lipid gel for topical treatment of colitis. We show that the gel is versatile and can host and release drugs of different polarities, including tofacitinib and tacrolimus, in a sustained manner. Further, we demonstrate its adherence to the colonic wall for at least 6 h, thus preventing leakage and improving drug bioavailability. Importantly, we find that loading known colitis treatment drugs into the temperature-triggered gel improves animal health in two mouse models of acute colitis. Overall, our temperature-triggered gel may prove beneficial in ameliorating colitis and decreasing adverse effects associated with systemic application of immunosuppressive treatments.

No abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease affecting the colonic mucosa. There is no cure for UC and its chronic relapsing/remitting nature strongly affects patient quality of life. Current treatment options frequently have significant side effects and remission rates are limited raising a demand for new treatment strategies. Novel therapeutic approaches that could maximize the drug concentration at the site of inflammation with minimal systemic exposure, like topical applications, would address this unmet clinical need. To date, few drug delivery systems (DDSs) have been designed to topically convey small molecules to the rectum and left-sided colon. Here, we developed and tested a drug delivery platform for topical treatment of UC based on a temperature-triggered in situ forming adhesive lipid gel (TIF-Gel). Due to its soft-gel consistency, its high encapsulation efficacy and its drug-controlled release, TIF-Gel suggests a more patient-friendly and effective application with respect to the rectal formulations currently available. Capitalizing on the biocompatible and biodegradable self-assembled structure of lipid mesophases (LMPs), we loaded TIF-Gel with tofacitinib (TOFA; an hydrophilic inhibitor of the enzymes Janus kinase 1 and 3) or TAC ( an hydrophobic immunosuppressive drug), both indicated in the treatment of UC. We designed and fully characterized our biocompatible lipid formulation in vitro and tested it in vivo using two different murine models of intestinal inflammation, in chemically-induced and T cell transfer-mediated models of colitis. Both approaches (TIF-Gel-TOFA and TIF-Gel-TAC) led to reduce either colitis disease severity or intestinal inflammation compared to vehicles, therefore showing therapeutic efficacy. Overall, our findings show that TIF-Gel can deliver drugs locally to the colonic mucosa to mitigate intestinal inflammatory disease in a pre-clinical model. They also suggest that, in a clinical setting, TIF-Gel might provide a patient-friendly approach to improve colitis while allowing a reduction of the adverse effects associated with a systemic therapy.