title: Enhancing the efficacy of drug-loaded nanocarriers against brain tumors by targeted radiation therapy.
abstract: Glioblastoma multiforme (GBM) is a common, usually lethal disease with a median survival of only ~15 months. It has proven resistant in clinical trials to chemotherapeutic agents such as paclitaxel that are highly effective in vitro, presumably because of impaired drug delivery across the tumor's blood-brain barrier (BBB). In an effort to increase paclitaxel delivery across the tumor BBB, we linked the drug to a novel filomicelle nanocarrier made with biodegradable poly(ethylene-glycol)-block-poly(ε-caprolactone-r-D,L-lactide) and used precisely collimated radiation therapy (RT) to disrupt the tumor BBB's permeability in an orthotopic mouse model of GBM. Using a non-invasive bioluminescent imaging technique to assess tumor burden and response to therapy in our model, we demonstrated that the drug-loaded nanocarrier (DLN) alone was ineffective against stereotactically implanted intracranial tumors yet was highly effective against GBM cells in culture and in tumors implanted into the flanks of mice. When targeted cranial RT was used to modulate the tumor BBB, the paclitaxel-loaded nanocarriers became effective against the intracranial tumors. Focused cranial RT improved DLN delivery into the intracranial tumors, significantly improving therapeutic outcomes. Tumor growth was delayed or halted, and survival was extended by >50% (p less than 0.05) compared to the results obtained with either RT or the DLN alone. Combinations of RT and chemotherapeutic agents linked to nanocarriers would appear to be an area for future investigations that could enhance outcomes in the treatment of human GBM.
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Baumann
authors.forename: Gary D
authors.initials: GD
authors.lastname: Kao
authors.forename: Abdullah
authors.initials: A
authors.lastname: Mahmud
authors.forename: Takamasa
authors.initials: T
authors.lastname: Harada
authors.forename: Joe
authors.initials: J
authors.lastname: Swift
authors.forename: Christina
authors.initials: C
authors.lastname: Chapman
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Xu
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Discher
authors.forename: Jay F
authors.initials: JF
authors.lastname: Dorsey
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D008856:Microscopy, Fluorescence; D049329:Nanostructures / Q000737:chemistry; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D049452:Green Fluorescent Proteins; D008156:Luciferases; D017239:Paclitaxel