New Transferrin Receptor-Targeting Conjugate Effectively Delivers DNA to Mouse Brain.

Delivery across the blood-brain barrier (BBB) is one of the most challenging tasks for modern biopharmaceutics. Many attempts have been taken, with only low delivery efficacies achieved so far. We report a new transferrin receptor-targeting (TfR) RNA aptamer conjugated to DSPE lipid that leads to an unprecedented effective uptake in the brain, with brain-to-serum ratios up to 6.5 in mice. This result is superior to recently published values of < 1 for antibody conjugates and nanovesicles, pointing to a successful combined effect of the increased lipophilicity and TfR targeting with the new RNA aptamer that our conjugate provides. Using fluorescence whole body imaging, polymerase-chain reaction (PCR) and fluorescence in situ hybridization, we confirm that the new conjugate delivers high amounts of DNA oligonucleotide to brains of Balb/cJ mice, and it is effective in human cells. There is no acute toxicity as verified with histopathological assessment of mice organs. The combination of properties demonstrated by our new conjugate makes it a highly potent delivery tool that can be applied in therapy of brain diseases incl. glioblastoma, neurogenerative diseases, and a broad range of brain infections.