d-Retroenantiomer of Quorum-Sensing Peptide-Modified Polymeric Micelles for Brain Tumor-Targeted Drug Delivery.

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. L WSW (SYPGWSW) is a recently reported quorum-sensing (QS) peptide that is able to efficiently cross the BBB. Even though linear L WSW traverses the BBB in vitro, its in vivo targeting ability has been greatly impaired due to proteolysis. Here, we developed a stable peptide, D WSW (D WD SD WD GD PD YD S), using the retro-inverso isomerization technique to achieve an enhanced antiglioma effect. In vitro studies have demonstrated that both the L WSW and D WSW peptides possessed excellent tumor-homing properties and barrier-penetration abilities, whereas D WSW exhibited exceptional stability in serum and maintained its targeting ability after serum preincubation. In vivo, D WSW-modified probes and micelles accumulated more efficiently in the glioma region in comparison with L WSW-modified probes and micelles because of full resistance to proteolysis in blood circulation. As expected, D WSW-modified paclitaxel (PTX)-loaded micelles (D WSW 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.