Convection Administered Drug Delivery to the Brain
Brain tumor patients face a poor prognosis despite significant advances in tumor imaging, neurosurgery and radiation therapy. Potent chemotherapeutic drugs fail when used to treat brain tumors because biochemical and physiological barriers limit drug delivery into the brain.
A retro-convection enhanced delivery (R-CED) method has been developed to improve the entry of intravenously administered therapeutics within solid brain tumors. R-CED uses an osmotic gradient to withdraw brain interstitial fluid in a controlled manner via an implanted microdialysis catheter. The transmembrane osmotic gradient increased the local tissue specific gravity in normal brain and induced movement of small proteins and nanoparticulates from the blood into normal brain and an orthotopic 9L tumor. The magnitude of the R-CED effect decreased to control values within six hours and did not cause acute anatomical damage beyond that of probe insertion.
A one hour R-CED treatment applied immediately after intravenous injection of liposomal doxorubicin ten days after tumor implantation showed no therapeutic effect compared to animals treated with intravenous PBS alone. The result suggests that R-CED may be more efficacious by modifying the R-CED probe design, increasing the R-CED treatment time, and improving the chemotherapeutic type and dosing schedule.
A mathematical model has been developed to predict the size of the R-CED affected region while varying the interstitial and vascular hydraulic conductivity and the fluid removal rate. The model enables the prediction of non-spherical flow patterns during simultaneous R-CED and CED or dual-probe CED via two catheters, guiding probe placement to achieve drug patterning and enabling wide distribution of therapeutics while sparing normal tissues. The alteration of solute flow was confirmed for dual-probe CED in vitro, but was difficult to visualize in vivo, where tissue inhomogeneities altered the flow from the idealized model prediction.
These studies demonstrate that R-CED is a viable and well-tolerated technique to enhance the distribution of systemically administered drugs in both the normal tissue-tumor margin as well as the central tumor core. They also highlight the opportunities to modify the R-CED design and enable future drug distribution and antitumor efficacy studies in larger tumors and possibly humans.