Tumor-penetrating Peptide Modified Liposome Drug Delivery System For Targeting Glioblastoma

Glioblastoma shows a high incidence rate, and the life times of thepatients were quite short. It is hardly to be cured by current clinicaltechniques. At present, the active targeting drug delivery system cannotpenetrate into the whole tumor tissue due to the poor permeability of thetargeting moiety in the tumor tissue. Neuropilin-1(NRP-1) is a receptoroverexpressed on both glioblastoma cells and tumor endothelium.RGERPPR peptide, the specific ligand of NRP-1, is a tumor-penetratingpeptide, able to penetrate through tumor vessels and tumor tissues. In thisstudy, we will adopt the “NRP-1mediated targeting” strategy, and studythe targeted therapy of glioblastoma by using the RGERPPR-conjugateddoxorubicin-loaded liposome delivery system. The study was conducted toverify our hypothesis that following intraveneous administration, theprepared liposomes specifically bind to NRP-1on glioblastomaendothelium, penetrate through tumor vessel and into the whole tumortissue. After that, being mediated by NRP-1on glioblastoma cells, theprepared liposomes enter tumor cells, and the loaded doxorubicin inhibitsthe tumor cell growth, thereby attaining the aim of targeted therapy ofglioblastoma.In this study, a tumor-penetrating peptide(RGERPPR), the specificligand of neuropilin-1overexpressed on glioblastoma and endothelial cells,was used as a targeting moiety to enhance the anti-glioblastoma effect ofdoxorubicin liposomes. Firstly, RGERPPR-PEG-DSPE was synthesizedand used to prepare the RGERPPR peptide-functionalized liposomes(RGE-LS), which showed vesicle sizes of around90nm and narrow sizedistributions. The cellular uptake and in vivo near-infrared fluorescence imaging test displayed that RGE-LS exhibited increased uptake byglioblastoma cells and intracranial glioblastoma tissues. The cytotoxicityassay and anti-glioblastoma study proved that RGERPPR functionalizationsignificantly enhanced the in vitro inhibitory effect of doxorubicinliposomes on glioblastoma cells and prolonged the median survival time ofnude mice bearing intracranial glioblastoma. Finally, theimmunofuorescence analysis evidenced that RGE-LS were able topenetrate through tumor vessels and stroma and deep into the whole tumortissue. The results indicated that tumor-penetrating peptidefunctionalization is an effective strategy for enhancing theanti-glioblastoma effect of doxorubicin liposomes.This study will provide a novel solution for the current dilemma ofactive targeted therapy of glioblastoma and other types of tumor.