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

Laboratory investigation

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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.

Article Information

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

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Coronal MR images showing the CED distribution of gadoteridol liposomes in 4 specific sites and the leakages associated with each infusion. A and B: Primate putamen infusion and corresponding sulcal leakage. C and D: Primate corona radiata infusion and corresponding sulcal leakage. E and F: Canine thalamus infusion and corresponding ventricular leakage. G and H: Canine tumor infusion and corresponding ventricular leakage.

  • View in gallery

    Graphs depicting the volume distributed (Vd) versus the volume infused (Vi) of 4 infusions that resulted in liposomal leakage. A: Primate putamen infusion. B: Primate corona radiata infusion. C: Canine thalamus infusion. D: Canine tumor infusion.

  • View in gallery

    Bar graph showing a comparison of the average slope (ΔVd/ΔVi) before and after leakage from 10 liposomal infusion cases. Standard error bars are shown.

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