DOTA Glycodendrimers as Cu(II) Complexing Agents and Their Dynamic Interaction Characteristics toward Liposomes.

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-N2O2 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.

Mucoadhesive 3D printed vaginal ovules to treat endometriosis and fibrotic uterine diseases.

Gynaecological health is a neglected field of research that includes conditions such as endometriosis, uterine fibroids, infertility, viral and bacterial infections, and cancers. There is a clinical need to develop dosage forms for gynecological diseases that increase efficacy and reduce side effects and explore new materials with properties tailored to the vaginal mucosa and milieu. Here, we developed a 3D printed semisolid vaginal ovule containing pirfenidone, a repurposed drug candidate for endometriosis. Vaginal drug delivery allows direct targeting of the reproductive organs via the first uterine pass effect, but vaginal dosage forms can be challenging to self-administer and retain in situ for periods of more than 1-3 h. We show that a semisoft alginate-based vaginal suppository manufactured using semisolid extrusion additive manufacturing is superior to vaginal ovules made using standard excipients. The 3D-printed ovule showed a controlled release profile of pirfenidone in vitro in standard and biorelevant release tests, as well as better mucoadhesive properties ex vivo. An exposure time of 24 h of pirfenidone to a monolayer culture of an endometriotic epithelial cell line, 12Z, is necessary to reduce the cells' metabolic activity, which demonstrates the need for a sustained release formulation of pirfenidone. 3D printing allowed us to formulate mucoadhesive polymers into a semisolid ovule with controlled release of pirfenidone. This work enables further preclinical and clinical studies into vaginally administered pirfenidone to assess its efficacy as a repurposed endometriosis treatment.

Temperature-triggered in situ forming lipid mesophase gel for local treatment of ulcerative colitis.

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.