Hemocompatible L-Type Amino acid Transporter 1 (LAT1)-Utilizing Prodrugs of Perforin Inhibitors Can Accumulate into the Pancreas and Alleviate Inflammation-induced Apoptosis

Chem Biol Interact. 2021 Jun 18:109560. doi: 10.1016/j.cbi.2021.109560. Online ahead of print.ABSTRACTCytolytic pore-forming protein, perforin, has been associated with autoimmune destruction of pancreatic β-cells in type 1 diabetes mellitus (T1DM) once released from CD8+ T cells. Curiously, perforinopathy has also been implicated in numerous brain diseases. Therefore, inhibitors of perforin have been in demand with targeted delivery in mind. L-Type amino acid transporter 1 (LAT1) is known to be expressed in both the above-mentioned target tissues, in the pancreas as well as in the brain. Thus, in the present study, the distribution of two LAT1-utilizing prodrugs of investigational perforin inhibitors into the pancreas was explored after intraperitoneal (i.p., 30 μmol/kg) bolus injection to mice. The effects of prodrug 1 were also studied in lipopolysaccharide (LPS)-induced in vitro (50 μg/ml) and in vivo (250 μg/kg x 3 days) apoptosis and pancreatitis models by determining the cellular apoptotic levels with human umbilical vein endothelial cells (HUVEC) and pancreatic caspase-3/-7 activity in mice. Furthermore, the biocompatibility of prodrug 1 was explored in human plasma and towards red blood cells. According to the results, both prodrugs were accumulated more effectively into the pancreas than their parent drugs (in addition to the brain that has been previously reported). Prodrug 1 (30 μmol/kg) also decreased the pancreatic caspase-3/-7 activity (52%) and with 2.5 Î...
Source: Chemico-Biological Interactions - Category: Molecular Biology Authors: Source Type: research