Real-time, image-guided, convection-enhanced delivery of interleukin 13 bound to pseudomonas exotoxin.
OBJECTIVE
To determine if the tumor-targeted cytotoxin interleukin 13 bound to Pseudomonas exotoxin (IL13-PE) could be delivered to the brainstem safely at therapeutic doses while monitoring its distribution in real-time using a surrogate magnetic resonance imaging tracer, we used convection-enhanced delivery to perfuse rat and primate brainstems with IL13-PE and gadolinium-bound albumin (Gd-albumin).


METHODS
Thirty rats underwent convective brainstem perfusion of IL13-PE (0.25, 0.5, or 10 microg/mL) or vehicle. Twelve primates underwent convective brainstem perfusion of either IL13-PE (0.25, 0.5, or 10 microg/mL; n = 8), co-infusion of 125I-IL13-PE and Gd-albumin (n = 2), or co-infusion of IL13-PE (0.5 microg/mL) and Gd-albumin (n = 2). The animals were permitted to survive for up to 28 days before sacrifice and histologic assessment.


RESULTS
Rats showed no evidence of toxicity at all doses. Primates showed no toxicity at 0.25 or 0.5 microg/mL but showed clinical and histologic toxicity at 10 microg/mL. Quantitative autoradiography confirmed that Gd-albumin precisely tracked IL13-PE anatomic distribution and accurately showed the volume of distribution.


CONCLUSIONS
IL13-PE can be delivered safely and effectively to the primate brainstem at therapeutic concentrations and over clinically relevant volumes using convection-enhanced delivery. Moreover, the distribution of IL13-PE can be accurately tracked by co-infusion of Gd-albumin using real-time magnetic resonance imaging.
Murad
Gregory J A
GJ
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland 20892-1414, USA.
Walbridge
Stuart
S
Morrison
Paul F
PF
Garmestani
Kayhan
K
Degen
Jeffrey W
JW
Brechbiel
Martin W
MW
Oldfield
Edward H
EH
Lonser
Russell R
RR
D036002:ADP Ribose Transferases / Q000009:adverse effects / Q000493:pharmacokinetics*; D000818:Animals; D001345:Autoradiography; D001427:Bacterial Toxins / Q000009:adverse effects / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier; D001933:Brain Stem / Q000737:chemistry*; D020295:Brain Stem Neoplasms / Q000188:drug therapy; D003287:Contrast Media / Q000008:administration & dosage; D018481:Convection; D004305:Dose-Response Relationship, Drug; D005098:Exotoxins / Q000009:adverse effects / Q000493:pharmacokinetics*; D005682:Gadolinium / Q000008:administration & dosage; D005910:Glioma / Q000188:drug therapy; D018793:Interleukin-13 / Q000009:adverse effects / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D046911:Macromolecular Substances; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000008:administration & dosage; D037521:Virulence Factors / Q000009:adverse effects / Q000493:pharmacokinetics*; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D003287:Contrast Media; D005098:Exotoxins; D005682:Gadolinium; D018793:Interleukin-13; D046911:Macromolecular Substances; D012709:Serum Albumin; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A