Detection of infusate leakage in the brain using real-time imaging of convection-enhanced delivery

Laboratory investigation

Vanja Varenika B.S. 1 , Peter Dickinson B.V.Sc., Ph.D. 2 , John Bringas B.S. 1 , Richard LeCouteur B.V.Sc., Ph.D. 2 , Robert Higgins D.V.M., Ph.D. 2 , John Park M.D. 1 , Massimo Fiandaca M.D. 1 , 3 , Mitchel Berger M.D. 1 , John Sampson M.D., Ph.D. 4 and Krystof Bankiewicz M.D., Ph.D. 1
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  • 1 Department of Neurological Surgery, University of California, San Francisco;
  • 2 Department of Surgical and Radiological Sciences, University of California, Davis, School of Veterinary Medicine, Davis, California;
  • 3 Department of Neurosurgery, LifeBridge Health Brain & Spine Institute, Baltimore, Maryland; and
  • 4 Division of Neurosurgery, Duke University Medical Center, Durham, North Carolina
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Object

The authors have shown that convection-enhanced delivery (CED) of gadoteridol-loaded liposomes (GDLs) into different regions of normal monkey brain results in predictable, widespread distribution of this tracking agent as detected by real-time MR imaging. They also have found that this tracking technique allows monitoring of the distribution of similar nanosized agents such as therapeutic liposomes and viral vectors. A limitation of this procedure is the unexpected leakage of liposomes out of targeted parenchyma or malignancies into sulci and ventricles. The aim of the present study was to evaluate the efficacy of CED after the onset of these types of leakage.

Methods

The authors documented this phenomenon in a study of 5 nonhuman primates and 7 canines, comprising 54 CED infusion sessions. Approximately 20% of these infusions resulted in leakage into cerebral ventricles or sulci. All of the infusions and leakage events were monitored with real-time MR imaging. The authors created volume-distributed versus volume-infused graphs for each infusion session. These graphs revealed the rate of distribution of GDL over the course of each infusion and allowed the authors to evaluate the progress of CED before and after leakage.

Results

The distribution of therapeutics within the target structure ceased to increase or resulted in significant attenuation after the onset of leakage.

Conclusions

An analysis of the cases in this study revealed that leakage undermines the efficacy of CED. These findings reiterate the importance of real-time MR imaging visualization during CED to ensure an accurate, robust distribution of therapeutic agents.

Abbreviations used in this paper: CED = convection-enhanced delivery; CSF = cerebrospinal fluid; DOPC = 1,2-dioleoyl-sn-glycero-3-phosphocholine; GDL = gadoteridol-loaded liposome; HEPES = 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid; PEG-DSG = 1,2-distearoyl-sn-glycero-3-[methoxy(polyethylene glycol)-2000.

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Contributor Notes

Address correspondence to: Krystof Bankiewicz, M.D., Ph.D., 1855 Folsom Street, Room 226, San Francisco, California 94103. email: Krystof.Bankiewicz@ucsf.edu.
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