FEK self‐assembled peptide hydrogels facilitate primary hepatocytes culture and pharmacokinetics screening

Abstract

A FEFEFKFK (FEK, F, phenylalaninyl; E, glutamyl; K, lysinyl)‐based self‐assembling peptide hydrogel (FEK‐SAPH) was developed to replace sandwich culture (SC) for improved culture of primary hepatocytes in vitro. Under neutral conditions, FEK self‐assembles to form β‐sheet nanofibers, which in turn form FEK‐SAPH. For the culture of rat primary hepatocytes (RPH), the use of FEK‐SAPH simplified operation steps and promoted excellent cell–cell interactions while maintaining the SC‐related RPH polarity trend. Compared with SC, FEK‐SAPH cultured RPH for 14 days, the bile duct network was formed, the secretion of albumin and urea was improved, and the metabolic clearance rate based on cytochrome P450 (CYPs) was comparable. In FEK‐SAPH culture, the expression level of the biliary efflux transporter bile salt export pump increased by 230.7%, while the biliary excretion index value of deuterium‐labeled sodium taurocholate (d8‐TCA) differed slightly from the SC value (72% and 77%, respectively, p = .0195). The inhibitory effect of cholestasis drugs on FEK‐SAPH was significantly higher than that of SC. In FEK‐SAPH, hepatoprotective drugs were more effective in antagonizing hepatotoxicity induced by lithocholic acid (LCA). FEK‐SAPH cultured RPH with hepatoprotective drugs can better recover from LCA‐induced damage. In summary, FEK‐SAPH can be used as a substitute for SC for pharmacokinetic screening to evaluate the drug absorption, disposition, metabolism, excretion, and toxicity (ADMET) in hepatocytes.

In situ stimulus-responsive self-assembled nanomaterials for drug delivery and disease treatment

“…10 In vivo self-assembled nanomedicines undergo blood circulation, tissue penetration, targeted accumulation, and elimination in vitro . 11 In contrast to in vitro self-assembled nanodrugs, in situ constructed self-assembled nanodrugs circulate in a molecular state, “self-assembly-assisted target” to the lesion site, 12 and accumulate in the pathological site through the aggregation/assembly-induced retention (AIR) effect, 13 which reduces the problems of rapid excretion and extensive metabolism, resulting in lower systemic toxicity. 14 Therefore, the in situ construction of stimuli-responsive self-assembled nanomaterials provides new ideas and strategies for diagnosing and treating major diseases such as cancer.…”