Imaging of Convective Drug Delivery in the Nervous System

Convection-enhanced delivery permits the direct homogeneous delivery of small- and large-molecular-weight putative therapeutics to the nervous system in a manner that bypasses the blood–nervous system barrier. The development of co-infused surrogate imaging tracers (for computed tomography and MRI) allows for the real-time, noninvasive monitoring of infusate distribution during convective delivery. Real-time image monitoring of convective distribution of therapeutic agents insures that targeted structures/nervous system regions are adequately perfused, enhances safety, informs efficacy (or lack thereof) of putative agents, and provides critical information regarding the properties of convection-enhanced delivery in normal and various pathologic tissue states.

Key points

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Direct convective delivery bypasses the blood–nervous system barrier and homogeneously distributes small- and large-molecular-weight compounds to the nervous system.
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Surrogate imaging tracers (computed tomography and MRI) permit real-time monitoring of convection-enhanced delivery to the nervous system.
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Real-time imaging ensures adequate convective delivery of therapeutics, enhances safety, informs efficacy, and provides insight into convective delivery properties.

Introduction

The rapidly expanding biological understanding of the pathologic mechanisms underlying a variety of neurologic disorders has led to the development of numerous promising putative therapeutics to treat ineffectively or untreatable neurologic diseases. Although these potentially therapeutic compounds have shown great promise during in vitro and in translational (animal) investigations, they have not realized clinical therapeutic success. A major obstacle to the safe and successful implementation of new therapeutic compounds for neurologic disease treatment has been the inability to provide their targeted and effective distribution to the nervous system across the blood–nervous system barrier (BNSB) using currently available delivery techniques (including systemic, intrathecal/intraventricular, or drug-impregnated polymer delivery).

Systemic drug delivery is limited by the BNSB, which permits only small (<400 Da molecular weight) and lipophilic molecules into the nervous system parenchyma. Intrathecal/intraventricular and polymer implantation delivery are driven by diffusion that limits drug distribution to 2 to 4 mm (with a steep exponential drop in concentration) from the drug exposed surface. Convection-enhanced delivery (CED) relies on infusate bulk flow and can be used to overcome the limitations of other delivery techniques to directly distribute therapeutic compounds to target regions in the nervous system in a manner that bypasses the BNSB. Recently, co-infused surrogate imaging tracers (computed tomography [CT] and MRI) have been developed to monitor convective delivery in real time.

Introduction

The rapidly expanding biological understanding of the pathologic mechanisms underlying a variety of neurologic disorders has led to the development of numerous promising putative therapeutics to treat ineffectively or untreatable neurologic diseases. Although these potentially therapeutic compounds have shown great promise during in vitro and in translational (animal) investigations, they have not realized clinical therapeutic success. A major obstacle to the safe and successful implementation of new therapeutic compounds for neurologic disease treatment has been the inability to provide their targeted and effective distribution to the nervous system across the blood–nervous system barrier (BNSB) using currently available delivery techniques (including systemic, intrathecal/intraventricular, or drug-impregnated polymer delivery).

Systemic drug delivery is limited by the BNSB, which permits only small (<400 Da molecular weight) and lipophilic molecules into the nervous system parenchyma. Intrathecal/intraventricular and polymer implantation delivery are driven by diffusion that limits drug distribution to 2 to 4 mm (with a steep exponential drop in concentration) from the drug exposed surface. Convection-enhanced delivery (CED) relies on infusate bulk flow and can be used to overcome the limitations of other delivery techniques to directly distribute therapeutic compounds to target regions in the nervous system in a manner that bypasses the BNSB. Recently, co-infused surrogate imaging tracers (computed tomography [CT] and MRI) have been developed to monitor convective delivery in real time.

Convection-enhanced delivery

The characteristics of convective delivery of infusate in the nervous system are based on bulk flow properties. The bulk flow (or convective flow) that drives CED is derived from a syringe pump that generates a small infusate hydrostatic pressure gradient that is transmitted through a noncompliant infusion apparatus to an infusion cannula. Based on its bulk flow properties, convective delivery reliably (with region-dependent volume of infusion/volume of tissue distribution ratios in the range of 2:1–10:1) and homogeneously (square-shaped distribution pattern) distributes infusate to targeted regions of the peripheral or central nervous system. Because infusate is distributed directly to the nervous system parenchyma via a cannula using CED, the BNSB is bypassed, and agents that do not penetrate this vascular barrier are ideally suited for CED, as they do not readily efflux back into the vascular system and remain sequestered on the abluminal (parenchymal) side of the BNSB for prolonged periods.

Imaging convective delivery

Surrogate Tracers

Real-time imaging convective drug delivery

Effective real-time imaging of convective drug delivery in the nervous system is critical for several reasons. First, it can confirm adequate and accurate drug distribution, which ensures that a targeted anatomic structure or region is sufficiently treated. Second, it informs understanding of drug efficacy (or lack thereof). Only by understanding if drug was effectively delivered, can efficacy be determined. Third, it enhances safety by making certain that drug delivery is limited to the targeted site. Fourth, data derived from infusions can be used to directly inform predictive infusate modeling, which could optimize cannula placement in the future. Finally, real-time imaging provides understanding of convective delivery properties in normal or diseased nervous system tissues. Better understanding of the properties of CED, including optimal rate of delivery, the effects of edema, volume loss in degenerative conditions, and anatomic boundaries/surfaces, will enhance delivery reproducibility and reliability.

Rationale for surrogate imaging tracers

Currently, the most developed, readily applicable and effective method for real-time imaging of CED is the use of surrogate imaging tracers. Surrogate imaging tracers are co-infused (rather than directly attached to drug) with putative therapeutics. These surrogate agents can be detected by CT scanning, MRI, or both methods during convective delivery. Features of surrogate imaging agents that are ideal or critical are that they include an excellent safety profile, can accurately track a wide range of co-infused therapeutic agents, are detected by noninvasive imaging methods, provide clear well-defined imaging with high spatial resolution, are readily available/developed, can be detected by widely available imaging techniques, and have no effect on co-infused drug action. Data from preclinical and clinical investigations have defined several CT and MRI surrogate agents.

CT scanning surrogate imaging tracers

Small- (iopamidol) and large- (iopanoic acid–labeled albumin; >70,000 Da) molecular-weight surrogate CT scanning tracers have been studied in rodent and nonhuman primate models using convective delivery. These surrogate imaging agents provided clear real-time well-defined imaging using CT scanning ( Fig. 1 ) without evidence of clinical or tissue toxicity. The tracking accuracy of the small (iopamidol) commercially available tracer, based on quantitative autoradiography, for a small (sucrose, 359 Da) and large molecule (dextran, 70,000 Da) infusate was excellent (19.7% and 7.5% difference in imaged volume vs actual distribution, respectively) ( Fig. 2 ). These studies demonstrated the safety, feasibility, accuracy, and utility of using a CT scanning tracer paradigm for convective drug delivery.

MRI surrogate tracers

Because small-molecular-weight magnetic resonance surrogate imaging tracers (gadolinium [Gd]-diethylenetriamine pentaacetic acid [Gd-DTPA], 983 Da, and gadoteridol, 559 Da) are commercially available and because these tracers can be used to track a wide range of putative therapeutic agents, they have been the best-studied surrogate imaging tracers. These compounds have been investigated extensively in rodent and nonhuman primate models. These surrogate MRI agents provided clear real-time, well-defined, high-resolution imaging using magnetic resonance scanning ( Fig. 3 ) without evidence of clinical or tissue toxicity. The tracking accuracy of these small-molecular-weight Gd-based compounds co-infused with small (muscimol, 114 Da) and large molecules (proteins and adeno-associated viruses, 24 nm; M13 bacteriophage, 900 nm) is excellent ( Fig. 4 ).