Delivery of boron agents to brain tumors is dependent on: (1) the plasma concentration profile ofthe drug, which depends upon the amount and route of administration, (2) the ability of the agent to traverse the BBB, (3) blood flow within the tumor, and (4) the lipophilicity of the drug. In general, a high steady-state blood concentration will maximize brain uptake, whereas rapid clearance will reduce it, except in the case of intra-arterial (ia) drug administration. Although the iv route currently is being used clinically to administer both BSH and BPA, this may not be ideal and other strategies may be needed to improve their delivery. Delivery of boron-containing drugs to extracranial tumors, such as head, neck, and liver cancer, presents a different set of problems, including non-specific uptake and retention in adjacent normal tissues.
Intra-arterial Administration With or Without Blood-Brain Barrier Disruption
As shown in experimental animal studies (30,31,134-136), enhancing the delivery of BPA and BSH can have a dramatic effect both on increasing tumor boron uptake and the efficacy of BNCT. This has been demonstrated in the F98 rat glioma model where intracarotid (ic) injection of either BPA or BSH doubled the tumor boron uptake compared to that obtained by iv injection (30). This was increased fourfold by disrupting the BBB by infusing a hyperosmotic (25%) solution of mannitol via the internal carotid artery. MST of animals that received either BPA or BSH ic with BBB-D were increased 295 and 117%, respectively, compared with irradiated controls (30). The best survival data were obtained using both BPA and BSH in combination, administered by ic injection with BBB-D. The MST was 140 d with a cure rate of 25%, compared with 41 d following iv injection with no longterm surviving animals (31). Similar data have been obtained using a rat model for melanoma metastatic to the brain. BPA was administered ic to nude rats bearing intracerebral implants of the human MRA 27 melanoma with or without BBB-D. The MSTs were 104 to 115 d with 30% long-term survivors compared with a MST of 42 d following iv administration (134). A similar enhancement in tumor boron uptake and survival was observed in F98 glioma bearing rats following ic infusion ofthe bradykinin agonist, RMP-7 (receptor mediated permeabilizer-7), and more recently called Cereport™ (136). In contrast to the increased tumor uptake, normal brain boron values at 2.5 h following ic injection were very similar for the iv and ic routes with or without BBB-D. Because BNCT is a binary system, normal brain boron levels only are of significance at the time of irradiation and high values at earlier time points are inconsequential. These studies have shown that a significant therapeutic gain can be achieved by optimizing boron drug delivery, and this should be important for both ongoing and future clinical trials using BPA and/or BSH.
Different strategies may be required for other low-molecular-weight boron containing compounds whose uptake is cell cycle dependent, such as boron containing nucleosides, where continuous administration over a period of days may be required. We recently have reported that direct it injection or CED of the borononucleoside N5-2OH (cpd 5) were both effective in selectively delivering potentially therapeutic amounts of boron to rats bearing intracerebral implants of the F98 glioma (60). Direct it injection or CED most likely will be necessary for a variety of high-molecular-weight delivery agents such as boronated MAbs and ligands such as EGF (129,134), as well as for low-molecular-weight agents such as nucleosides and porphyrins (134). Recent studies have shown that CED of a boronated porphyrin derivative similar to cpd 7, designated H2DCP, resulted in the highest tumor boron values and T:Br and T:Bl ratios that we have seen with any of the boron agents that we have ever studied (135).
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