title: Convection-enhancement delivery of liposomal formulation of oxaliplatin shows less toxicity than oxaliplatin yet maintains a similar median survival time in F98 glioma-bearing rat model.
abstract: Results of clinical trials with oxaliplatin in treating glioblastoma are dismal. Previous works showed that intravenous (i.v.) delivery of oxaliplatin did not increase the survival of F98 glioma-bearing Fisher rats. Low accumulation of the drug in tumor cells is presumed to be responsible for the lack of antitumor effect. In the present study, convection-enhanced delivery (CED) was used to directly inject oxaliplatin in brain tumor implanted in rats. Since CED can led to severe toxicity, the liposomal formulation of oxaliplatin (Lipoxal™) was also assessed. The maximum tolerated dose (MTD) of oxaliplatin was 10 μg, while that of Lipoxal™ was increased by 3-times reaching 30 μg. Median survival time (MeST) of F98 glioma-bearing rats injected with 10 μg oxaliplatin by CED was 31 days, 7.5 days longer than untreated control (p = 0.0002); while CED of 30 μg Lipoxal™ reached the same result. Compared to previous study on i.v. delivery of these drugs, their injection by CED significantly increased their tumoral accumulations as well as MeSTs in the F98 glioma bearing rat model. The addition of radiotherapy (15 Gy) to CED of oxaliplatin or Lipoxal™ increased the MeST by 4.0 and 3.0 days, respectively. The timing of radiotherapy (4 h or 24 h after CED) produced similar results. However, the treatment was better tolerated when radiotherapy was performed 24 h after CED. In conclusion, a better tumoral accumulation was achieved when oxaliplatin and Lipoxal™ were injected by CED. The liposomal encapsulation of oxaliplatin reduced its toxic, while maintaining its antitumor potential.
authors.affiliation: Center for Research in Radiotherapy, Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Heath Science, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors.forename: Minghan
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of Surgery, Division of Neurosurgery, Centre Hospitalier Universitaire de Sherbrooke (D.F.), Sherbrooke, Québec, J1H 5N4, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Fortin
authors.affiliation: Center for Research in Radiotherapy, Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Heath Science, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada. Benoit.Paquette@USherbrooke.ca.
authors.forename: Benoit
authors.initials: B
authors.lastname: Paquette
authors.affiliation: Center for Research in Radiotherapy, Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Heath Science, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors.forename: Léon
authors.initials: L
authors.lastname: Sanche
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D003131:Combined Modality Therapy; D016503:Drug Delivery Systems; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D000077150:Oxaliplatin; D051381:Rats; D011916:Rats, Inbred F344; D015996:Survival Rate; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin
keywords: Convection-enhanced delivery; Fischer rats; Glioblastoma; Liposomal formulation of oxaliplatin; Lipoxal™; Radiation therapy