Labradimil

Tight junction (TJ) modulation is a promising approach for improving drug bioavailability by enhancing the absorption of active pharmaceutical ingredients. However, the application of many different test methods to determine the efficacy of new TJ modulators (TJMs) or to assess different compounds is accompanied by a lack of comparable results, reducing the rational evaluation and commercial marketing of these pharmaceutical excipients. The establishment of unified testing methods can fill this gap and offers the opportunity to compare results from different laboratories. Furthermore, the calculation of a TJ modulation score allows the objective comparison of TJ modulators and facilitates the selection of appropriate candidates. In this study, eight well-known TJ modulators were tested with a focus on four different in vitro bioassays carried out with MDCK cells. The extent of TJ modulation was determined by transepithelial electric resistance (TEER) measurements and permeability studies with mannitol. To evaluate tolerability, cell viability (MTT) and cytotoxicity (CellTox^™ Green) assays were performed, and TEER regeneration was monitored for 24 h after exposure. With the exception of labradimil, seven TJ modulators caused significant TEER reduction of up to 100 %. For five compounds, an enhancement of mannitol permeation was observed. As expected, first-generation enhancers exhibited lower cell compatibility than mechanism-based modulators. Based on the experimental results of this study, for the first time, an evaluation system (tight junction modulator scoring system, TJMSS) is presented that provides a ranking of the tested modulators depending on weighted parameters. Such a system offers the possibility of rational formulation development for drugs requiring improved absorption.

Liposomes with Cereport (RMP-7) and transferrin (Tf) (RMP-7/Tf/liposomes) were employed to target the blood-brain barrier (BBB) and to inhibit the degeneration of neurons insulted with fibrillar β-amyloid peptide 1-42 (Aβ1-42). Neuron growth factor (NGF)-encapsulated RMP-7/Tf/liposomes (RMP-7/Tf/NGF-liposomes) were used to permeate a monolayer of human brain-microvascular endothelial cells (HBMECs) regulated by human astrocytes (HAs) and to treat Aβ1-42 -attacked SK-N-MC cells. An increase in RMT-7 concentration increased the particle size, zeta potential, propidium iodide (PI) permeability, and NGF permeability, but decreased the cross-linking efficiency of RMT-7, viability of HBMECs and HAs, and transendothelial electrical resistance (TEER). In addition, an increase in Tf concentration enhanced the particle size, viability of HBMECs, HAs, and SK-N-MC cells, PI permeability, and NGF permeability, but reduced the zeta potential, cross-linking efficiency of RMT-7 and Tf, and TEER. RMP-7/Tf/NGF-liposomes can transport NGF across the BBB and improve the neuroprotection for Alzheimer's disease therapy in preclinical trials.