Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part II: Arborizing Catheter for Convection-Enhanced Delivery in Tissue Phantoms

Abstract

Convection-enhanced delivery (CED) is the process of local, pressuredriven flow of drugs into brain parenchyma containing tumor tissue, resulting in greater distribution of the infused drugs compared to diffusion-dependent therapies. Nevertheless, even with the advantage of CED over simple diffusion, the large volumes necessary to target entire tumors and peritumor volumes have been previously unachievable with currently available catheters. We present a novel, multiport, arborizing catheter designed specifically for improving drug distribution into the brain. We evaluated the performance of the arborizing catheter by quantifying volume dispersed (V d ) and mean distribution ratios (V d :V i ) in infusion studies Novel Catheter for Drug Delivery 360 using agarose brain phantoms and compared results to a single-port catheter. Three experimental groups were evaluated: (i) single-port infusions at 1 μL/min; (ii) single-port infusions at 7 μL/min; and (iii) seven-port arborizing catheter infusions at 1 μL/min/port. Significantly greater V d was calculated for the arborizing catheter group (10.47 ± 1.07 cm 3 ) compared with the single-port catheter groups at the low-and high-flow rates (2.36 ± 0.21 cm 3 and 5.14 ± 0.56 cm 3 ), respectively. V d :V i for the arborizing catheter was 37% lower than the single-port catheter at 1 μL/min, but 100% greater than the single-port catheter at 7 μL/min. The multiport, arborizing catheter produced the greatest distribution of the infusate, which would be advantageous for CED; however, it did not exhibit the greatest distribution ratio, likely due to overlapping distribution volumes from the multiple individual ports.

Controlled Catheter Movement Affects Dye Dispersal Volume in Agarose Gel Brain Phantoms

“…A shadowgraphy setup similar to that used previously [29] allowed visualization of the dye V d . Briefly, two agarose gel phantoms were placed on an acrylic stage in front of a light-diffusing shade and behind a complementary metal-oxide-semiconductor camera (Rebel T1i, Cannon Inc., Ohta-ku, Tokyo, Japan), allowing for two experiments to be conducted at the same time.…”

“…Briefly, two agarose gel phantoms were placed on an acrylic stage in front of a light-diffusing shade and behind a complementary metal-oxide-semiconductor camera (Rebel T1i, Cannon Inc., Ohta-ku, Tokyo, Japan), allowing for two experiments to be conducted at the same time. The agarose gel phantoms were kept at 25 • C, consistent with previous studies [29,38,41] and below the gel's gelling temperature of 36 • C. Two catheters were supported by two linear stages in series-the first stage allowed for manual deployment, while the second stage allowed for remote deployment, as shown in Figure 1. For all groups, the catheters were first manually inserted into the gel phantoms through the reflux arresting tubing using the manual linear stage, such that they just began protruding from the reflux arresting tip.…”

“…After the catheters were inserted, an indigo carmine dye solution (1% w/w) was infused at 1 µL/min for 100 min using a programmable syringe pump (Chemyx Fusion 100, Chemyx, Austin, TX, USA). The flowrate of 1 µL/min was chosen in order to minimize the potential of backflow and is the rage of flowrates range typically used in CED infusion studies [16,[24][25][26][27][28][29][30]39,40,43]. Once the infusion was started, the continuously retracting or advancing catheters were moved 25 mm at a rate of 0.25 mm/min and the intermittent advancing catheters were inserted an additional 6 mm with 1 mm of retraction every 16 min, for a total additional insertion of 25 mm.…”

“…In order to combat the low delivery volumes found in clinical trials, focus was directed to improving the catheter design. Many of these devices focused on limiting backflow using a step change [24][25][26][27][28] and adding multiple ports within a single primary cannula to increase total infusion volume [29,30]. However, exploration of alternative methods to increase the volume dispersed (V d ), such as catheter movement during infusion, has been sparse.…”

Multireceptor targeting of glioblastoma

“… 12 , 18 Newly engineered catheters optimize drug delivery by preventing infusate refluxes, utilize multiple tips or hollow fibers especially designed to deliver therapy to most of the tumor volume. 17 , 19 , 20 Importantly, a real-time monitoring of infusion helps to ascertain proper drug delivery while the deliveries are shortened. Also of high importance, the nonenhancing tumors can be infused.…”