Targeted concurrent and sequential delivery of chemotherapeutic and antiangiogenic agents to the brain by using drug-loaded nanofibrous membranes

Abstract

Yuan-Yun Tseng,1,2 Tao-Chieh Yang,3 Yi-Chuan Wang,4 Wei-Hwa Lee,5 Tzu-Min Chang,4 Yi-Chuan Kau,6 Shih-Jung Liu4,7 1Division of Neurosurgery, Department of Surgery, Shuang Ho Hospital, 2Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 3Department of Neurosurgery, Asia University Hospital, Taichung, 4Department of Mechanical Engineering, Chang Gung University, Taoyuan, 5Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei, 6Department of Anesthesiology, 7Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan Abstract: Glioblastoma is the most frequent and devastating primary brain tumor. Surgery followed by radiotherapy with concomitant and adjuvant chemotherapy is the standard of care for patients with glioblastoma. Chemotherapy is ineffective, because of the low therapeutic levels of pharmaceuticals in tumor tissues and the well-known tumor-cell resistance to chemotherapy. Therefore, we developed bilayered poly(d,l)-lactide-co-glycolide nanofibrous membranes that enabled the sequential and sustained release of chemotherapeutic and antiangiogenic agents by employing an electrospinning technique. The release characteristics of embedded drugs were determined by employing an in vitro elution technique and high-performance liquid chromato­graphy. The experimental results showed that the fabricated nanofibers showed a sequential drug-eluting behavior, with the release of high drug levels of chemotherapeutic carmustine, irinotecan, and cisplatin from day 3, followed by the release of high concentrations of the antiangiogenic combretastatin from day 21. Biodegradable multidrug-eluting nanofibrous membranes were then dispersed into the cerebral cavity of rats by craniectomy, and the in vivo release characteristics of the pharmaceuticals from the membranes were investigated. The results suggested that the nanofibrous membranes released high concentrations of pharmaceuticals for more than 8 weeks in the cerebral parenchyma of rats. The result of histological analysis demonstrated developmental atrophy of brains with no inflammation. Biodegradable nanofibrous membranes can be manufactured for long-term sequential transport of different chemotherapeutic and antiangiogenic agents in the brain, which can potentially improve the treatment of glioblastoma multiforme and prevent toxic effects due to systemic administration. Keywords: nanofibrous membrane, poly(d,l)-lactide-co-glycolide (PLGA), glioblastoma multiforme (GBM), chemotherapy, targeted therapy, antiangiogenesis

Keywords

• Nanofibrous membrane
• poly[(d
• l)-lactide-co-glycolide] (PLGA)
• glioblastoma multiforme (GBM)
• chemotherapy
• targeted therapy
• antiangiogenesis