Non-immunogenic, low-toxicity and effective glioma targeting MTI-31 liposomes

Liposomes with peptide motifs have been successfully used in glioma-targeted delivery of various general chemotherapy agents. However, their use for the encapsulation of low-toxicity molecularly targeted anticancer agents has been limited. In the present study, we aimed to assess the efficacy and safety of a novel low-toxicity mTORC1/mTORC2 inhibitor (MTI-31) as a treatment for glioma when encapsulated in appropriate liposomes. Since some of the peptide-modified liposomes have been determined to be immunogenic and may have life-threatening consequences in mice, an immunogenicity-based investigation with candidate liposomal carriers was conducted. Following this study, ^DVAP (^DP^DA^DV^DR^DT^DN^DS) modified liposomes (^DVAP-liposomes) were identified as an immunologically safe carrier and therefore utilized for MTI-31 encapsulation. ^DVAP is a tumor homing peptide exhibiting high binding affinity to glucose regulated protein 78 (GRP78) overexpressed in glioma, glioma stem cells, vasculogenic mimicry and neovasculature. Modification of liposomes with ^DVAP imparts a glioma-directing property. In vitro, the developed ^DVAP-liposomes/MTI-31 were efficiently internalized by U87 cells and consequently showed a potent antiproliferation effect. In vivo, the safety and anti-glioma efficiency of ^DVAP-liposomes/MTI-31 were validated in intracranial glioma bearing BALB/c nude mice. While showing both systemic and immunological safety, ^DVAP-liposome/MTI-31 treatment resulted in a significant improvement in the median survival time (24.5 days for saline, 26 days for free MTI-31, 25 days for liposomes/MTI-31 and 36 days for ^DVAP-liposome/MTI-31). The results highlight MTI-31 as an effective anti-glioma agent when encapsulated in non-immunogenic glioma-targeted liposomes, which may contribute to the development of better anti-glioma treatment.