title: In vivo evaluation of intracellular drug-nanocarriers infused into intracranial tumours by convection-enhanced delivery: distribution and radiosensitisation efficacy.
abstract: The objective of the present study was to investigate the interest of convection-enhanced delivery (CED) for the administration of a nanocarrier-based radiosensitizing chemotherapy in the rat brain. Pursuing on newly developed lipid nanocapsules (LNC) that can be internalised within brain tumour cells, we studied their intracerebral distribution when labelled with fluorescent Nile red (NR). As paclitaxel (Px) represents an interesting radiosensitiser, we also evaluated the potential radiosensitising effects of Px-loaded LNC administered through CED in the 9L intracranial rat glioblastoma model. The distribution study demonstrated that CED injection of NR-loaded LNC (NR-LNC) improved significantly the volume of distribution of NR when matched with simple injection (by about 150 fold). It also reveals that the LNC perfusion of a whole tumour forming area inside the CNS (6 days after implantation of 10(3) 9L cells) is achievable through CED injection, whilst preserving the ability of LNC to reach the intracellular space of encountered tumour cells. Having established an animal model of encephalic irradiation close to the clinic (18 Gray in three fractions of six Gray at days 8, 11 and 14 after 9L cell implantation) we proved the feasibility of the combination of CED for the administration of drug-loaded LNC with external beam therapy. Although a single CED injection of Px-LNC at low Px dose (375 mug/kg of bodyweight) gave the best median survival (twice that of untreated controls), it underlines the need for optimisation. Hence, the possibility of grafting recognition moieties onto the LNC surface combined to their biocompatibility must be beneficial.
authors.affiliation: Inserm U646, Université d'Angers, 10 rue André Boquel, 49100, Angers, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vinchon-Petit
authors.forename: Delphine
authors.initials: D
authors.lastname: Jarnet
authors.forename: Archibald
authors.initials: A
authors.lastname: Paillard
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Benoit
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Garcion
authors.forename: Philippe
authors.initials: P
authors.lastname: Menei
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D002469:Cell Separation; D003131:Combined Modality Therapy; D018481:Convection; D005260:Female; D005434:Flow Cytometry; D005909:Glioblastoma / Q000628:therapy*; D018613:Microscopy, Confocal; D053769:Nanocapsules / Q000737:chemistry; D036103:Nanotechnology / Q000379:methods; D017239:Paclitaxel / Q000008:administration & dosage*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D053769:Nanocapsules; D011838:Radiation-Sensitizing Agents; D017239:Paclitaxel