Convection-Enhanced Drug Delivery: Increased Efficacy and Magnetic Resonance Image Monitoring

Abstract

Convection-enhanced drug delivery (CED) is a novel approach to directly deliver drugs into brain tissue and brain tumors. It is based on delivering a continuous infusion of drugs via intracranial catheters, enabling convective distribution of high drug concentrations over large volumes of the target tissue while avoiding systemic toxicity. Efficient formation of convection depends on various physical and physiologic variables. Previous convection-based clinical trials showed significant diversity in the extent of convection among patients and drugs. Monitoring convection has proven to be an essential, yet difficult task. The current study describes the application of magnetic resonance imaging for immediate assessment of convection efficiency and early assessment of cytotoxic tissue response in a rat brain model. Immediate assessment of infusate distribution was obtained by mixing Gd-diethylenetriaminepentaacetic acid in the infusate prior to infusion. Early assessment of cytotoxic tissue response was obtained by subsequent diffusion-weighted magnetic resonance imaging. In addition, the latter imaging methodologies were used to establish the correlation between CED extent and infusate's viscosity. It was found that low-viscosity infusates tend to backflow along the catheter track, whereas highviscosity infusates tend to form efficient convection. These results suggest that CED formation and extent may be significantly improved by increasing the infusate's viscosities, thus increasing treatment effects. (Cancer Res 2005; 65(15): 6858-63)

Salirasib (farnesyl thiosalicylic acid) for brain tumor treatment: a convection-enhanced drug delivery study in rats

“…The cytotoxic response of brain tissue to therapeutic agents infused via CED could be assessed at an early stage by means of subsequent T 2 -weighted and diffusion-weighted MRI. Our data suggested, moreover, that drug distribution can be significantly improved by increasing the infusate viscosity where optimal infusate distribution was achieved with 10% sucrose (12).…”

“…This solution was diluted to create a final concentration of 50 Amol/L salirasib in PBS containing 10% sucrose based on our previous experiments (12). For preparation of the control vehicle, we used ethanolic PBS without salirasib.…”

“…Procedure-related toxicity (such as hydrocephalus caused by infusion into the ventricles) was assessed by T 2 -weighted MRI acquired immediately after the treatment. Early and late tissue toxicity were assessed by T 2 -weighted and diffusion-weighted images acquired 24 h and 2 weeks post-treatment (12). In addition, the rats' weight was monitored throughout the 2-week follow-up period.…”

“…Calculation of Extent of CED The gadolinium enhancement obtained from T 1 -weighted MRI reflects the infusate distribution in the rat brain (12). Thus, the volume (in cm 3 ) of infusate distribution was calculated from the T 1 -weighted MRI acquired immediately after CED treatment.…”

“…In a recent study aimed at integrating drugs into the CED model, we showed that the readily available magnetic resonance imaging (MRI) contrast agent Gd-DTPA could be used as a surrogate marker for immediate assessment of convection efficiency and infusate distribution simply by being mixed with the infusate before infusion (12). The cytotoxic response of brain tissue to therapeutic agents infused via CED could be assessed at an early stage by means of subsequent T 2 -weighted and diffusion-weighted MRI.…”