title: Convection-enhanced delivery of free gadolinium with the recombinant immunotoxin MR1-1.
abstract: A major obstacle in glioblastoma (GBM) therapy is the restrictive nature of the blood-brain barrier (BBB). Convection-enhanced delivery (CED) is a novel method of drug administration which allows direct parenchymal infusion of therapeutics, bypassing the BBB. MR1-1 is a novel recombinant immunotoxin that targets the GBM tumor-specific antigen EGFRvIII and can be delivered via CED infusion. However, drug distribution via CED varies dramatically, which necessitates active monitoring. Gadolinium conjugated to diethylenetriamine penta-acetic acid (Gd-DTPA) is a commonly used MRI contrast agent which can be co-infused with therapies using CED and may be useful in monitoring infusion leak and early distribution. Forty immunocompetent rats were implanted with intracerebral cannulas that were connected to osmotic pumps and subsequently randomized into four groups that each received 0.2% human serum albumin (HSA) mixed with a different experimental infusion: (1) 25 ng/ml MR1-1; (2) 0.1 micromol/ml Gd-DTPA; (3) 25 ng/ml MR1-1 and 0.1 micromol/ml Gd-DTPA; (4) 250 ng/ml MR1-1 and 0.1 micromol/ml Gd-DTPA. The rats were monitored clinically for 6 weeks then necropsied and histologically assessed for CNS toxicity. All rats survived the entirety of the study without clinical or histological toxicity attributable to the study drugs. There was no statistically significant difference in weight change over time among groups (P > 0.999). MR1-1 co-infused with Gd-DTPA via CED is safe in the long-term setting in a pre-clinical animal model. Our data supports the use of Gd-DTPA, as a surrogate tracer, co-infused with MR1-1 for drug distribution monitoring in patients with GBM.
authors.affiliation: School of Medicine, Duke University Medical Center, DUMC, Box 3050, 220 Sands Building, Research Drive, Durham, NC 27710, USA. dale.ding@duke.edu
authors.forename: Dale
authors.initials: D
authors.lastname: Ding
authors.forename: Charles W
authors.initials: CW
authors.lastname: Kanaly
authors.forename: Darrell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Cummings
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.forename: Raghu
authors.initials: R
authors.lastname: Raghavan
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001921:Brain / Q000187:drug effects; D003287:Contrast Media / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018481:Convection; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004815:Epidermal Growth Factor / Q000276:immunology; D019786:Gadolinium DTPA / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007121:Immunocompetence; D000922:Immunotoxins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008279:Magnetic Resonance Imaging; D011498:Protein Precursors / Q000276:immunology; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D003287:Contrast Media; D000922:Immunotoxins; D011498:Protein Precursors; C042652:epidermal growth factor precursor; D004815:Epidermal Growth Factor; D019786:Gadolinium DTPA