Application of luteolin nanomicelles anti-glioma effect with improvement in vitro and in vivo.

Songping Zheng,Xiaoxiao Liu,Yuquan Wei,Cong Wu,Xiang Gao,Chao You,Yanhui Liu,Yan Teng,Yi Wang,Xiang Wang,Jiagang Liu,Ting Yu,Yuzhu Hu,Yongzhong Cheng

doi:10.18632/oncotarget.18019

Abstract

Glioblastoma multiforme (GBM) is one of the most common and malignant tumor. Luteolin, a polyphenolic compound, has been proposed to have anti-tumor activity against various cancers. However, the greatest obstacle in the administration of luteolin is its hydrophobicity as well as the low oral bioavailability. In this study, we formulated luteolin-loaded MPEG-PCL (Luteolin/MPEG-PCL) micelles aiming to improve its solubility in aqueous solution and investigate the anti-tumor effect on glioma in vitro and in vivo. The spherical Luteolin/MPEG-PCL micelles were completely dispersible in normal saline and could release luteolin in a sustained manner in vitro. We demonstrated that Luteolin/MPEG-PCL micelles had stronger cytotoxicity and induced a higher percentage of apoptosis in C6 and U87 cells than free luteolin in vitro. The immunohistochemical study revealed that Luteolin/MPEG-PCL micelles induced more glioma cell apoptosis than free luteolin and inhibited neovascularization in tumor tissues. The Pro-caspase9 and Bcl-2 down-regulation and cleaved-caspase9 and Bax up-regulation suggested that luteolin induced apoptosis via the mitochondrial pathway in vitro. What is more, we found the drug could cumulated much more in the nano-drug group than free drug group through imaging in vivo. In conclusion, the Luteolin/MPEG-PCL micelles have the potential clinical application in glioma chemotherapy.

Highlights

Glioma is the most common primary malignant brain tumor in children and adults, and has been notoriously known to be a great challenge for clinical treatment
Recent research showed that glioma cells over-express the multi-drug resistance (MDR) transporters which lead to the extruding of agents resulting in the phenomenon of chemoresistance [5]
The size was confirmed by TEM (Figure 1C), which was consistent with the DLS results

Summary

Introduction

Glioma is the most common primary malignant brain tumor in children and adults, and has been notoriously known to be a great challenge for clinical treatment. Treated with comprehensive therapy which consists of surgical resection followed by radiotherapy and chemotherapy, the median survival time of patients with GBM is only 15-17 months [2,3,4]. GMB features a high proliferation activity and a diffuse nature having a tendency to invade surrounding brain tissues. The effective accumulation of chemotherapy agents in the central nervous system is limited because of the blockage of blood–brain barrier (BBB). Recent research showed that glioma cells over-express the multi-drug resistance (MDR) transporters which lead to the extruding of agents resulting in the phenomenon of chemoresistance [5]. More effective chemotherapy drugs are sorely in need

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Conclusion