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

in Angewandte Chemie (International ed. in English) by Min-Sun Song, Adrian H Bustos, Lise Bredahl Bastue, Justas Mikutavicius, Piotr Swiderski, Kelly J Clemens, Nagy Habib, John Rossi, Kira Astakhova

TLDR

  • Researchers develop a new RNA aptamer conjugate that effectively delivers DNA oligonucleotides to the brain, offering a promising solution for therapy of brain diseases.
  • The conjugate achieves high brain-to-serum ratios and is effective in human cells, with no acute toxicity.
  • The study demonstrates the potential of targeted delivery approaches in the treatment of brain diseases and highlights the need for further research in this area.

Abstract

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 broad range of brain infections.

Overview

  • Delivery across the blood-brain barrier (BBB) is one of the most challenging tasks in biopharmaceutics, with low delivery efficacies achieved so far.
  • The study reports the development of a new transferrin receptor-targeting (TfR) RNA aptamer conjugated to DSPE lipid, which achieves an unprecedented effective uptake in the brain.
  • The main objective of the study is to develop a novel delivery tool for therapy of brain diseases, including glioblastoma, neurogenerative diseases, and various brain infections.

Comparative Analysis & Findings

  • The new conjugate achieves a brain-to-serum ratio of up to 6.5 in mice, significantly higher than recently published values of < 1 for antibody conjugates and nanovesicles.
  • The study confirms the effective delivery of DNA oligonucleotide to the brains of Balb/cJ mice using fluorescence whole body imaging, PCR, and fluorescence in situ hybridization.
  • The new conjugate demonstrates efficacy in human cells, with no acute toxicity as verified by histopathological assessment of mice organs.

Implications and Future Directions

  • The new conjugate demonstrates a high potential as a delivery tool for therapy of brain diseases, offering a promising solution for the treatment of glioblastoma, neurogenerative diseases, and brain infections.
  • Future studies can focus on optimizing the properties of the conjugate for specific disease applications and exploring its potential for combination therapies.
  • The successful development of this conjugate highlights the importance of targeted delivery approaches in the treatment of brain diseases, emphasizing the need for further research in this area.
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