Synergetic therapy of glioma mediated by a dual delivery system loading \u03b1-mangostin and doxorubicin through cell cycle arrest and apoptotic pathways

Wen Nie,Xin Zan,Mengni Ran,Ting Yu,Yan Ju,Zehua Hong,Xiang Gao,Tingting Yang,Yihong He

doi:10.1038/s41419-020-03133-1

Abstract

Two of the biggest hurdles in the deployment of chemotherapeutics against glioma is a poor drug concentration at the tumor site and serious side effects to normal tissues. Nanocarriers delivering different drugs are considered to be one of the most promising alternatives. In this study, a dual delivery system (methoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL)) loaded with α-mangostin (α-m) and doxorubicin (Dox) was decorated and constructed by self-assembly to determine its ability to treat glioma. Molecular dynamics simulations showed that MPEG-PCL could provide ideal interaction positions for both α-m and Dox, indicating that the two drugs could be loaded into MPEG-PCL. Based on the in vitro results, MPEG-PCL loaded with α-m and Dox (α-m-Dox/M) with a size of 25.68 nm and a potential of −1.51 mV was demonstrated to significantly inhibit the growth and promote apoptosis in Gl261, C6 and U87 cells, and the effects of the combination were better than each compound alone. The mechanisms involved in the suppression of glioma cell growth were blockage of the cell cycle in S phase by inhibition of CDK2/cyclin E1 and promotion of apoptosis through the Bcl-2/Bax pathway. The synergetic effects of α-m-Dox/M effectively inhibited tumor growth and prolonged survival time without toxicity in mouse glioma models by inducing glioma apoptosis, inhibiting glioma proliferation and limiting tumor angiogenesis. In conclusion, a codelivery system was synthesized to deliver α-m and Dox to the glioma, thereby suppressing the development of glioma by the mechanisms of cell cycle arrest and cellular apoptosis, which demonstrated the potential of this system to improve the chemotherapy response of glioma.

Highlights

Glioma, a neoplasm originating from neuroepithelial cells, accounts for approximately 75% of the malignant primary brain cancers in adults[1,2]
Computational molecular dynamics simulation analysis We used computer simulations to explore the interactions between α-m, Dox and the MPEG-PCL copolymer
By changing the location and adjusting the conformation, α-m and Dox found their proper places on MPEG-PCL for combination

Summary

Introduction

A neoplasm originating from neuroepithelial cells, accounts for approximately 75% of the malignant primary brain cancers in adults[1,2]. Despite decades of sustained efforts and advances in surgical treatment, radiotherapy and chemotherapy, the current therapies are Official journal of the Cell Death Differentiation Association. Doxorubicin (Dox) is an anthracycline drug that has been used as a first-line chemotherapeutic agent for cancer therapy since the 1960s6. Dox is toxic to normal tissues and organs such as the heart and brain[12,13,14]. Due to its toxicity to normal tissues, its clinical applications have been greatly limited. In recent years, efforts have been made to study Dox delivery systems to deliver drugs and reduce its toxicity and side effects on normal cells[15,16,17]

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