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

Xiaoyi Wang; Nana Meng; Songli Wang; Yanyu Zhang; Linwei Lu; Ruifeng Wang; Huitong Ruan; Kuan Jiang; Huan Wang; Danni Ran; Changyou Zhan; Ker Yu; Diane J Burgess; Weiyue Lu

doi:10.1016/j.jconrel.2019.11.005

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. Epub 2019 Nov 12.

Authors

Xiaoyi Wang¹, Nana Meng¹, Songli Wang¹, Yanyu Zhang¹, Linwei Lu², Ruifeng Wang¹, Huitong Ruan¹, Kuan Jiang¹, Huan Wang¹, Danni Ran¹, Changyou Zhan³, Ker Yu⁴, Diane J Burgess⁵, Weiyue Lu⁶

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 (^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.

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

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / pharmacology
Antineoplastic Agents / toxicity
Brain Neoplasms / drug therapy*
Brain Neoplasms / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Delivery Systems
Endoplasmic Reticulum Chaperone BiP
Glioma / drug therapy*
Glioma / pathology
Humans
Liposomes
Male
Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
Mechanistic Target of Rapamycin Complex 2 / antagonists & inhibitors
Mice
Mice, Inbred BALB C
Mice, Inbred ICR
Mice, Nude
Peptides / chemistry
Survival Rate
Time Factors

Substances

Antineoplastic Agents
Endoplasmic Reticulum Chaperone BiP
HSPA5 protein, human
Hspa5 protein, mouse
Liposomes
Peptides
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2