e development of nanostructures for therapeutic purpose is rapidly growing, following the results obtained in vivo in animal models and in the clinical trials. Unfortunately, the potential therapeutic efficacy is not completely exploited, yet. is is mainly due to the fast clearance of the nanostructures in the body. Nanoparticles and the liver have a unique interaction because the liver represents one of the major barriers for drug delivery. is interaction becomes even more relevant and complex when the drug delivery strategies employing nanostructures are proposed for the therapy of liver diseases, such as hepatocellular carcinoma (HCC). In this case, the selective delivery of therapeutic nanoparticles to the tumor microenvironment collides with the tendency of nanostructures to be quickly eliminated by the organ. e design of a new therapeutic approach based on nanoparticles to treat HCC has to particularly take into consideration passive and active mechanisms to avoid or delay liver elimination and to specifically address cancer cells or the cancer microenvironment. is review will analyze the different aspects concerning the dual role of the liver, both as an organ carrying out a clearance activity for the nanostructures and as target for therapeutic strategies for HCC treatment.

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Complement activation is largely implicated in the pathogenesis of several clinical conditions and its therapeutic neutralization has proven effective in preventing tissue and organ damage. A problem that still needs to be solved in the therapeutic control of complement-mediated diseases is how to avoid side effects associated with chronic neutralization of the complement system, in particular, the increased risk of infections. We addressed this issue developing a strategy based on the preferential delivery of a C5 complement inhibitor to the organ involved in the pathologic process. To this end, we generated Ergidina, a neutralizing recombinant anti-C5 human antibody coupled with a cyclic-RGD peptide, with a distinctive homing property for ischemic endothelial cells and effective in controlling tissue damage in a rat model of renal ischemia/reperfusion injury (IRI). As a result of its preferential localization on renal endothelium, the molecule induced complete inhibition of complement activation at tissue level, and local protection from complement-mediated tissue damage without affecting circulating C5. The ex vivo binding of Ergidina to surgically removed kidney exposed to cold ischemia supports its therapeutic use to prevent posttransplant IRI leading to delay of graft function. Moreover, the finding that the ex vivo binding of Ergidina was not restricted to the kidney, but was also seen on ischemic heart, suggests that this RGD-targeted anti-C5 antibody may represent a useful tool to treat organs prior to transplantation. Based on this evidence, we propose preliminary data showing that Ergidina is a novel targeted drug to prevent complement activation on the endothelium of ischemic kidney.

Prediction of biliary excretion is a challenge for drug discovery scientists due to the lack of in vitro assays. This study explores the possibility of establishing a simple assay to predict in vivo biliary excretion via the mrp2 transport system. In vitro mrp2 activity was determined by measuring the ATP-dependent uptake of 5(6)-carboxy-2',7'-dichlorofluorescein (CDCF) in canalicular plasma membrane vesicles (cLPM) from rat livers. The CDCF uptake was time- and concentration-dependent (K(m) of 2.2 ± 0.3 µM and V(max) of 115 ± 26 pmol/mg/min) and strongly inhibited by the mrp2 inhibitors, benzbromarone, MK-571, and cyclosporine A, with IC(50) values ≤ 1.1 µM. Low inhibition of CDCF uptake by taurocholate (BSEP inhibitor; 57 µM) and digoxin (P-gp inhibitor; 101 µM) demonstrated assay specificity towards mrp2. A highly significant correlation (r(2) = 0.959) between the in vitro IC(50) values from the described mrp2 assay and in vivo biliary excretion in rats was observed using 10 literature compounds. This study demonstrated, for the first time, that a high throughput assay could be established with the capability of predicting biliary excretion in the rat using CDCF as a substrate.

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