1. Academic Validation
  2. Non-immunogenic, low-toxicity and effective glioma targeting MTI-31 liposomes

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

  • J Control Release. 2019 Dec 28;316:381-392. doi: 10.1016/j.jconrel.2019.11.005.
Xiaoyi Wang 1 Nana Meng 1 Songli Wang 1 Yanyu Zhang 1 Linwei Lu 2 Ruifeng Wang 1 Huitong Ruan 1 Kuan Jiang 1 Huan Wang 1 Danni Ran 1 Changyou Zhan 3 Ker Yu 4 Diane J Burgess 5 Weiyue Lu 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education and PLA, Shanghai 201203, China.
  • 2 The Department of Integrative Medicine, Huashan Hospital, Fudan University, and The Institutes of Integrative Medicine of Fudan University, Shanghai 200041, China.
  • 3 Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education and PLA, Shanghai 201203, China; Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai 200433, China.
  • 4 Department of Pharmacology, Fudan University School of Pharmacy, Shanghai 201203, China.
  • 5 School of Pharmacy, University of Connecticut, Storrs, CT 06269, United States of America.
  • 6 Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education and PLA, Shanghai 201203, China; The Department of Integrative Medicine, Huashan Hospital, Fudan University, and The Institutes of Integrative Medicine of Fudan University, Shanghai 200041, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China; Minhang Branch, Zhongshan Hospital and Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201199, China. Electronic address: wylu@shmu.edu.cn.
Abstract

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 (DPDADVDRDTDNDS) 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.

Keywords

(D)VAP; Anti-glioma efficiency; Immunogenicity; Liposomes; MTI-31; Molecularly targeted anticancer agents.

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