Development of Low-Density Lipoprotein Receptor-Targeted Liposomes for Enhanced Accumulation in Ischemia/Reperfusion Environment.

Cerebral ischemia/reperfusion (I/R) injury caused by resumed blood flow to an infarcted area contributes to poor patient prognosis due to a lack of treatment strategies. While the blood-brain barrier (BBB) is the greatest barrier for drug delivery to the brain, temporary disruption to the BBB after brain I/R injury allows for delivery of cerebroprotective drug-encapsulated nanoparticles into the brain parenchyma. However, issues remain with delivering drugs to the I/R region using nanoparticles, such as the limited therapeutic time window due to BBB repair over time. To overcome these challenges, we developed nanoparticles specifically targeting the I/R environment. Human umbilical vein endothelial cells (HUVECs) were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R), an in vitro I/R model. Low-density lipoprotein receptor (LDLR) mRNA was upregulated early during the reoxygenation process. Furthermore, immunostaining of OGD/R-treated cells showed an increase in LDLR expression. Next, we constructed a peptide that mimics the LDLR binding recognition site on LDL, and modified liposomes to display the peptide on their surface. Peptide-modified liposomes showed targeting ability to the LDLR on cells. Accumulation of peptide-modified liposomes was significantly increased in OGD/R treated cells compared with controls, and was reduced by blocking LDLR using its antibody. These results demonstrate upregulation of LDLR and LDLR-mediated liposome uptake in OGD/R stressed cells. In conclusion, LDLR binding recognition site mimicking peptide-modified liposomes are a useful drug carrier that can recognize I/R injured endothelial cells.