<scp>d</scp>-Retroenantiomer of Quorum-Sensing Peptide-Modified Polymeric Micelles for Brain Tumor-Targeted Drug Delivery

Abstract

Compared to that of other tumors, various barriers, such as the blood-brain barrier (BBB), enzymatic barriers, and the blood-brain tumor barrier, severely impede the successful treatment of gliomas. Peptide ligands were frequently used as targeting moieties to mediate brain tumor-targeted drug delivery. ^LWSW (SYPGWSW) is a recently reported quorum-sensing (QS) peptide that is able to efficiently cross the BBB. Even though linear ^LWSW traverses the BBB in vitro, its in vivo targeting ability has been greatly impaired due to proteolysis. Here, we developed a stable peptide, ^DWSW (^DW^DS^DW^DG^DP^DY^DS), using the retro-inverso isomerization technique to achieve an enhanced antiglioma effect. In vitro studies have demonstrated that both the ^LWSW and ^DWSW peptides possessed excellent tumor-homing properties and barrier-penetration abilities, whereas ^DWSW exhibited exceptional stability in serum and maintained its targeting ability after serum preincubation. In vivo, ^DWSW-modified probes and micelles accumulated more efficiently in the glioma region in comparison with ^LWSW-modified probes and micelles because of full resistance to proteolysis in blood circulation. As expected, ^DWSW-modified paclitaxel (PTX)-loaded micelles (^DWSW Micelle/PTX) exhibited the longest median survival time among glioma-bearing nude mice. Our results suggested that the QS peptide appears to be a promising targeting moiety, with potential applications in glioma-targeted drug delivery.