Convection Enhanced Delivery

Convection-Enhanced Delivery (CED), by which therapeutic agents are directly infused into the brain, is an innovative method to increase their uptake and distribution.166_168 Under normal physiological conditions, interstitial fluids move through the brain by both convection and diffusion. Diffusion of a drug in tissue depends upon its molecular weight, ionic charge and its concentration gradient within normal tissue and the tumor. The higher the molecular weight of the drug, the more positively charged the ionic species and the lower its concentration, the slower its diffusion. For example, diffusion of antibody into a tumor requires 3 d to diffuse 1 mm from the point of origin. Unlike diffusion, however, convection or "bulk" flow results from a pressure gradient that is independent of the molecular weight of the substance. CED potentially can improve the targeting of both LMW and HMW molecules, as well as liposomes, to the central nervous system by applying a pressure gradient to establish bulk flow during interstitial infusion. The volume of distribution (Vd) is a linear function of the volume of the infusate (Vi). CED has been used to efficiently deliver drugs and HMW agents such as mAbs and toxin fusion proteins to brain tumors.168_170 CED can provide more homogenous dispersion of the agent and at higher concentrations than otherwise would be attainable by i.v. injection.165 For example, in our own studies, CED of 125I-labeled EGF to F98EGFR glioma-bearing rats resulted in 47% I.D./g of the bioconjugate localizing in the tumor compared to 10% I.D./g in normal brain at 24 h following administration. The corresponding boron values were 22 and 2.9_4.9 mg/g, respectively.76 Based on these results, therapy studies were initiated. F98EGFR glioma-bearing rats that received BD_EGF by CED had a MST of 53 +13 d compared to 40 + 5 d for animals that received BPA i.v.73 Similar studies have been carried out using either boronated cetuximab (IMC-C225) or the mAb L8A4,171,172 which is specifically directed against the tumor-specific mutant isoform, EGFRvIII, and comparable results were obtained.173 Direct intracerebral administration of these and other HMW agents by CED has opened up the possibility that they actually could be used clinically, since CED is being used to administer radiolabeled antibodies, toxin fusion proteins, and gene vectors to patients with GBM. It is only a matter of time before this approach also will be used to deliver both LMW and HMW boron-containing agents for NCT.

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