Convection enhanced delivery of different molecular weight tracers of gadolinium-tagged polylysine

Convection enhanced delivery (CED) is a powerful method of circumventing the blood-brain barrier (BBB) to deliver therapeutic compounds directly to the CNS. While inferring the CED distribution of a therapeutic compound by imaging a magnetic resonance (MR)-sensitive tracer has many advantages, however how the compound distribution is affected by the features of the delivery system, its target tissue, and its molecular properties, such as its binding characteristics, charge, and molecular weight (MW) are not fully understood. We used MR imaging of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA)-tagged polylysine compounds of various MW, in vitro and in vivo, to measure the dependence of compounds MW on CED distribution. For the in vitro studies, the correlation between volume of distribution (Vd) as a function of MW was determined by measuring the T1 of the infused tracers, into 0.6% agarose gels through a multiport catheter. The compounds distributed in the gels inversely proportional to their MW, consistent with convection and unobstructed diffusion through a porous media. For the in vivo studies, Gd-DTPA tagged compounds were infused into the non-human primate putamen, via an implanted multiport catheter connected to a MedStream™ pump, programmed to deliver a predetermined volume with alternating on-off periods to take advantage of the convective and diffusive contributions to Vd. Unlike the gel studies, the higher MW polylysine-tracer infusions did not freely distribute from the multiport catheter in the putamen, suggesting that distribution was impeded by other properties that should also be considered in future tracer design and CED infusion protocols.