The in vivo anti-fibrotic function of calcium sensitive receptor (CaSR) modulating poly(p-dioxanone-co-L-phenylalanine) prodrug

In present study, the apoptosis induction and proliferation suppression effects of L-phenylalanine (L-Phe) on fibroblasts were confirmed. The action sites of L-Phe on fibroblasts suppression were deduced to be calcium sensitive receptor (CaSR) which could cause the release of endoplasmic reticulum (ER) Ca2+ stores; disruption of intracellular Ca2+ homeostasis triggers cell apoptosis via the ER or mitochondrial pathways. The down-regulation of CaSR were observed after the application of L-Phe, and the results those L-Phe triggered the increasing of intracellular Ca2+ concentration and calcineurin expression, and then the apoptosis and increasing Cl fraction of fibroblasts have verified our deduction. Hence, L-Phe could be seen as a kind of anti-fibrotic drugs for the crucial participation of fibroblast in the occurrence of fibrosis. And then, poly(p-dioxanone-co-L-phenylalanine) (PDPA) which could prolong the in-vivo anti fibrotic effect of L-Phe for the sustained release of L-Phe during its degradation could be treated as anti fibrotic polymer prodrugs. Based on the above, the in vivo anti-fibrotic function of PDPA was evaluated in rabbit ear scarring, rat peritoneum lipopolysaccharide, and rat sidewall defect/cecum abrasion models. PDPA reduced skin scarring and suppressed peritoneal fibrosis and post operation adhesion as well as secretion of transforming growth factor-beta 1 in injured tissue. These results indicate that PDPA is an effective agent for preventing fibrosis following tissue injury. (C) 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.