title: A thermal gel depot for local delivery of paclitaxel to treat experimental brain tumors in rats.
abstract: OBJECTIVE
  Paclitaxel, a cellular proliferation inhibitor/radiation sensitizer, while effective against gliomas in vitro, has poor CNS penetration and dose-limiting toxicities when administered systemically. OncoGel (paclitaxel in Re-Gel) provides controlled local paclitaxel release when placed into the CNS. The authors evaluated the safety and efficacy of OncoGel in rats with intracranial 9L gliosarcoma.
  
  
  METHODS
  Safety studies included intracranial delivery of increasing volumes of ReGel and OncoGel containing 1.5 (OncoGel 1.5) or 6.3 (OncoGel 6.3) mg/ml paclitaxel. An in vivo radiolabeled biodistribution study was performed in 18 Fischer-344 rats to determine intracerebral distribution. Efficacy studies compared overall survival for controls, ReGel only, radiation therapy only, OncoGel 6.3, or OncoGel 6.3 in combination with radiation therapy. ReGel and OncoGel 6.3 were delivered either simultaneously with tumor implantation (Day 0) or 5 days later (Day 5). Radiation therapy was given on Day 5.
  
  
  RESULTS
  Control and ReGel animals died of tumor within 17 days. Survival significantly increased in the Onco-Gel 6.3 group on Day 0 (median 31 days; p = 0.0001), in the OncoGel 6.3 group on Day 5 (median 17 days; p = 0.02), and in the radiation therapy-only group (median 26 days; p = 0.0001) compared with controls. Animals receiving both OncoGel and radiation therapy had the longest median survival: 83 days in the group with radiation therapy combined with OncoGel 6.3 on Day 0, and 32 days in the group combined with OncoGel 6.3 on Day 5 (p = 0.0001 vs controls). After 120 days, 37.5% of the animals in the OncoGel Day 0 group, 37.5% of animals in the OncoGel 6.3 Day 0 in combination with radiation therapy group, and 12.5% of the animals in the OncoGel 6.3 on Day 5 in combination with radiation therapy group were alive. In the biodistribution study, measurable radioactivity was observed throughout the ipsilateral hemisphere up to 3 weeks after the OncoGel injection, with the most radioactivity detected 3 hours after injection. The highest dose of radioactivity observed in the contralateral hemisphere was at the Day 3 time point.
  
  
  CONCLUSIONS
  OncoGel containing 6.3 mg/ml of paclitaxel is safe for intracranial injection in rats and effective when administered on Day 0. When combined with radiation therapy, the combination was more effective than either therapy alone and should be studied clinically for the treatment of malignant glioma.
authors.affiliation: Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. btyler@jhmi.edu
authors.forename: Betty
authors.initials: B
authors.lastname: Tyler
authors.forename: Kirk D
authors.initials: KD
authors.lastname: Fowers
authors.forename: Khan W
authors.initials: KW
authors.lastname: Li
authors.forename: Violette Renard
authors.initials: VR
authors.lastname: Recinos
authors.forename: Justin M
authors.initials: JM
authors.lastname: Caplan
authors.forename: Alia
authors.initials: A
authors.lastname: Hdeib
authors.forename: Rachel
authors.initials: R
authors.lastname: Grossman
authors.forename: Luca
authors.initials: L
authors.lastname: Basaldella
authors.forename: Kimon
authors.initials: K
authors.lastname: Bekelis
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pradilla
authors.forename: Federico
authors.initials: F
authors.lastname: Legnani
authors.forename: Henry
authors.initials: H
authors.lastname: Brem
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005782:Gels; D018316:Gliosarcoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015552:Injections, Intralesional; D053208:Kaplan-Meier Estimate; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005782:Gels; D017239:Paclitaxel