Evaluating infusate parameters for direct drug delivery to the brainstem: a comparative study of convection-enhanced delivery versus osmotic pump delivery

Abstract

Objective: Convection-enhanced delivery (CED) and osmotic pump delivery both have been promoted as promising techniques to deliver drugs to pediatric diffuse intrinsic pontine gliomas (DIPGs). Correspondingly, the aim of this study was to understand how infusate molecular weight (MW), duration of delivery, and mechanism of delivery (CED or osmotic pump) affect volume of distribution (Vd) in the brainstem, to better inform drug selection and delivery in future DIPG investigations.

Methods: A series of in vivo experiments were conducted using rat models. CED and osmotic pump delivery systems were surgically implanted in the brainstem, and different MW fluorescent dextran beads were infused either once (acute) or daily for 5 days (chronic) in a volume infused (Vi). Brainstems were harvested after the last infusion, and Vd was quantified using serial sectioning and fluorescence imaging.

Results: Fluorescence imaging showed infusate uptake within the brainstem for both systems without complication. A significant inverse relationship was observed between infusate MW and Vd in all settings, which was distinctly exponential in nature in the setting of acute delivery across the 570-Da to 150-kDa range. Chronic duration and CED technique resulted in significantly greater Vd compared to acute duration or osmotic pump delivery, respectively. When accounting for Vi, acute infusion yielded significantly greater Vd/Vi than chronic infusion. The distribution in CED versus osmotic pump delivery was significantly affected by infusate MW at higher weights.

Conclusions: Here the authors demonstrate that infusate MW, duration of infusion, and infusion mechanism all impact the Vd of an infused agent and should be considered when selecting drugs and infusion parameters for novel investigations to treat DIPGs.

Keywords: BBB = blood-brain barrier; BLI = bioluminescence imaging; CED; CED = convection-enhanced delivery; DIPG; DIPG = diffuse intrinsic pontine glioma; FITC = fluorescein isothiocyanate; MW = molecular weight; PDX = patient-derived xenograft; Vd = volume of distribution; Vi = volume infused; brainstem; convection-enhanced delivery; diffuse intrinsic pontine glioma; molecular weight; osmotic pump; volume of distribution.

FIG. 1.

Representative CED (A) and osmotic pump (B) setups of the models.

FIG. 2.

Representative fluorescence (green areas) images of brainstem distribution using 10-kDa FITC-dextran beads after a single 90-μl infusion by CED (A) and 24-hour infusion by osmotic pump delivery (B). Anatomical exploration following CED in the brainstem demonstrated fluorescent parenchymal regions and blood vessels distal from the site of cannulation (C) with distribution along blood vessels (red arrow) and pial interfaces (red arrowheads) observed at higher magnification (D). A summative collage of 7-mm slices following CED with no evidence of reflux (E).

FIG. 3.

Graphs showing inversely proportional relationship between infusate MW and V_d in multiple settings. A: In the 3- to 20-kDa range, this relationship was linear (R² = 0.99 in all settings). B: For acute CED and osmotic pump over a broader range, 570 Da up to 150 kDa, this relationship was better modeled by exponential decay regression (R² = 0.91 for acute CED and 0.96 for acute osmotic pump).

FIG. 4.

Bar graphs showing comparison of V_d after acute versus chronic infusion by CED (A) and osmotic pump delivery (B) grouped by infusate MW. *p < 0.05.

FIG. 5.

Bar graphs showing comparison of V_d after CED versus osmotic pump delivery infusion in either an acute setting (panel A, 1.5 hours CED, 24 hours of osmotic pump delivery) or a chronic setting (panel B, 1.5 hours CED daily for 5 days, 5 continuous days of osmotic pump delivery) grouped by infusate MW. *p < 0.05.

FIG. 6.

Acute CED in an orthotopic PDX DIPG rodent model. A: Formation of DIPG was assessed with weekly 3D BLI. B: After the tumor had reached an appropriate size, a CED cannula was inserted and placement was confirmed by CT imaging superimposed on maximal BLI. C: Microscopic evaluation after acute CED administration of a 20-kDa infusate confirmed V_d and distribution across the entire tumor region.