Advanced interstitial chemotherapy combined with targeted treatment of malignant glioma in rats by using drug-loaded nanofibrous membranes

// Yuan-Yun Tseng 1, 2 , Chen-Hsing Su 3 , Shun-Tai Yang 1, 2 , Yin-Chen Huang 4 , Wei-Hwa Lee 5 , Yi-Chuan Wang 6 , Shou-Cheng Liu 6 , Shih-Jung Liu 6, 7 1 Division of Neurosurgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan 2 Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 3 Department of Neurosurgery, Chung Shan Medical University Hospital, Taichung, Taiwan 4 Department of Neurosurgery, Chang Gung Memorial Hospital-Chiayi, Chang Gung University College of Medicine, Tao-Yuan, Taiwan 5 Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan 6 Department of Mechanical Engineering, Chang Gung University, Tao-Yuan, Taiwan 7 Department of Orthopedics, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan Correspondence to: Shih-Jung Liu, email: shihjung@mail.cgu.edu.tw Keywords: glioblastoma multiforme (GBM), chemotherapy, targeted therapy, nanofiber, antiangiogenesis Received: March 06, 2016     Accepted: June 27, 2016     Published: August 1, 2016 ABSTRACT Glioblastoma multiforme (GBM), the most prevalent and malignant form of a primary brain tumour, is resistant to chemotherapy. In this study, we concurrently loaded three chemotherapeutic agents [bis-chloroethylnitrosourea, irinotecan, and cisplatin; BIC] into 50:50 poly[(d,l)-lactide-co-glycolide] (PLGA) nanofibres and an antiangiogenic agent (combretastatin) into 75:25 PLGA nanofibres [BIC and combretastatin (BICC)/PLGA]. The BICC/PLGA nanofibrous membranes were surgically implanted onto the brain surfaces of healthy rats for conducting pharmacodynamic studies and onto C6 glioma-bearing rats for estimating the therapeutic efficacy. The chemotherapeutic agents were rapidly released from the 50:50 PLGA nanofibres after implantation, followed by the release of combretastatin (approximately 2 weeks later) from the 75:25 PLGA nanofibres. All drug concentrations remained higher in brain tissues than in the blood for more than 8 weeks. The experimental results, including attenuated malignancy, retarded tumour growth, and prolonged survival in tumour-bearing rats, demonstrated the efficacy of the BICC/PLGA nanofibrous membranes. Furthermore, the efficacy of BIC/PLGA and BICC/PLGA nanofibrous membranes was compared. The BICC/PLGA nanofibrous membranes more efficiently retarded the tumour growth and attenuated the malignancy of C6 glioma-bearing rats. Moreover, the addition of combretastatin did not significantly change the drug release behaviour of the BIC/PLGA nanofibrous membranes. The present advanced and novel interstitial chemotherapy and targeted treatment provide a potential strategy and regimen for treating GBM.