2. Academic Validation
  3. 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.
PMID: 31730912 DOI: 10.1016/j.jconrel.2019.11.005
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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