A novel peptide ligand RAP12 of LRP1 for glioma targeted drug delivery

The receptor associated protein (RAP) is a 39 kDa chaperone protein, binding tightly to low-density lipoprotein receptor-related protein-1 (LRP1) that is overexpressed in glioma, tumor neovasculature, vasculogenic mimicry (VM), the blood–brain barrier (BBB) and the blood–brain tumor barrier (BBTB). Herein, we miniaturized the RAP protein into a short peptide RAP12 (EAKIEKHNHYQK) aiding by computer-aided peptide design technique. RAP12 contained the essential lysines at the positions 253 and 256. The binding affinity of RAP12 to LRP1 was theoretically and experimentally evaluated. In cellular level, RAP12 could effectively internalize into U87, HUVEC and bEnd.3 cells. When modified on the surface of PEG–PLA micelles (RAP12-PEG–PLA), RAP12 could effectively facilitate the penetration of micelles through the BBB/BBTB in vitro/vivo. Paclitaxel-loaded RAP12-PEG–PLA could remarkably inhibit the growth of glioma cells and the formation of tumor neovasculature and VM, significantly prolong the median survival time of nude mice bearing intracranial glioma in comparison to model mice treated with plain micelles or Taxol. These results suggested that the RAP12 held the potential for multifunctional glioma-targeted drug delivery.