title: Targeted concurrent and sequential delivery of chemotherapeutic and antiangiogenic agents to the brain by using drug-loaded nanofibrous membranes.
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 anti-angiogenic agents in the brain, which can potentially improve the treatment of glioblastoma multiforme and prevent toxic effects due to systemic administration.
authors.affiliation: Division of Neurosurgery, Department of Surgery, Shuang Ho Hospital; Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei.
authors.forename: Yuan-Yun
authors.initials: YY
authors.lastname: Tseng
authors.affiliation: Department of Neurosurgery, Asia University Hospital, Taichung.
authors.forename: Tao-Chieh
authors.initials: TC
authors.lastname: Yang
authors.affiliation: Department of Mechanical Engineering, Chang Gung University, Taoyuan.
authors.forename: Yi-Chuan
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei.
authors.forename: Wei-Hwa
authors.initials: WH
authors.lastname: Lee
authors.affiliation: Department of Mechanical Engineering, Chang Gung University, Taoyuan.
authors.forename: Tzu-Min
authors.initials: TM
authors.lastname: Chang
authors.affiliation: Department of Anesthesiology.
authors.forename: Yi-Chuan
authors.initials: YC
authors.lastname: Kau
authors.affiliation: Department of Mechanical Engineering, Chang Gung University, Taoyuan; Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Shih-Jung
authors.initials: SJ
authors.lastname: Liu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D016503:Drug Delivery Systems; D065546:Drug Liberation; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008567:Membranes, Artificial; D057139:Nanofibers / Q000737:chemistry*; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D005904:Glial Fibrillary Acidic Protein; D008567:Membranes, Artificial
keywords: antiangiogenesis; chemotherapy; glioblastoma multiforme (GBM); nanofibrous membrane; poly(dl)-lactide-co-glycolide (PLGA); targeted therapy