Carrier Systems Designed to Increase Permeation Across the BBB

Because AS-ODNs are often large, highly polar molecules, their transport across the BBB by way of passive diffusion is likely to be low. Many studies assumed that AS-ODNs would not cross the BBB without the aid of either a carrier protein or modification of the BBB itself. Carrier systems designed to

Fig. 2. Various AS-ODN analogs. (A) R* represents a variable group. If R* = oxygen atom (O), then this would depict an endogenous phosphodiester AS-ODN. If R* = sulfur atom (S), then this would depict a phosphorothioate antisense analog. If R* = methyl group (CH3), then this would depict a methylphosphonate antisense analog. (B) Structure of a PNA.

enhance transport across the BBB include antisense complexed with biotin, glycosylated polycations, or antibodies directed at receptors present within the BBB endothelium (36,37).

For example, in a study by Wu et al. (37), antisense molecules injected intravenously into rats were delivered to the brain via attachment to biotin. The modified antisense formed a complex with streptavidin molecules attached to an antibody directed at the rat transferrin receptor, which is present in the BBB under normal circumstances. On binding to the receptor, the antisense/ antibody complex would be transported across the BBB and delivered to the target tissue.

The BBB itself has also been a target for modifications aimed at increasing antisense delivery to the CNS. The BBB's permeability can be increased when certain vasoactive agents are introduced (38-40) . For example, bradykinin has been shown to increase permeability through a mechanism that involves B2 receptors and nitric oxide (41,42). Koga et al. (43) showed that intracarotid infusion of bradykinin increased delivery of AS-ODN into brain tumors. This type of delivery system allows therapeutic agents to be infused systemically and then delivered to malignant tumors of the brain without the level of disruption that occurs with other approaches to opening the BBB.

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