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In vivo delivery of transcription factors with multifunctional oligonucleotides

In vivo delivery of transcription factors with multifunctional oligonucleotides. Murthy Laboratory U.C. Berkeley Department of Bioengineering. Nrf2 plays a central role in protecting cells from oxidative stress. DNA Assembled Recombinant Transcription Factor Delivery (DARTs). Gal. Gal. Gal.

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In vivo delivery of transcription factors with multifunctional oligonucleotides

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  1. In vivo delivery of transcription factors with multifunctional oligonucleotides Murthy Laboratory U.C. Berkeley Department of Bioengineering

  2. Nrf2 plays a central role in protecting cells from oxidative stress

  3. DNA Assembled Recombinant Transcription Factor Delivery (DARTs) Gal Gal Gal Gal Endosomal disruption labile linkage Galactose Nrf2 promoter sequence DART

  4. DARTs are designed to deliver Nrf2 DART-Nrf2 Receptor mediated endocytosis Unmasked hydrophobic domain pH 5 in endosome Hydrolyzed DART Nrf2 release in cytoplasm

  5. DARTs undergo pH sensitive hydrolysis

  6. DARTs are pH sensitive membrane disruptive agents

  7. DARTs can deliver Nrf2 to cells Nrf2 DART-Nrf2

  8. DARTscan deliver Nrf2 to hepatocytes and transcribe downstream genes DART-Nrf2 Free Nrf2 Control HO1 NQO1 GCLC GAPDH

  9. DARTs are designed to deliver Nrf2 and treat liver disease

  10. DARTscan deliver Nrf2 in vivo and rescue mice from drug induced liver toxicity APAP - + + +

  11. Infection Imaging Diagnosing infections at an early stage is a central challenge in medicine

  12. The maltodextrin transporter is an ideal target for imaging bacteria MDPs Maltodextrin Transporter Ning et al. Nature Materials2011, 10(8), 602-607.

  13. MDPs are robustly internalized by bacteria MDP-1 mM / CFU SA EC PA BS

  14. Saline p s-1 cm-2 * 107 EC 107EC Saline MDPs can image bacteria in vivo MDP-2 Ning et al. Nature Materials2011, 10(8), 602-607.

  15. Maltohexaose-18F (MH18F) for PET imaging CuI, DIPEA, DMF, rt • K18F, CH3CN, 110 ⁰C; • NaOH, H2O, 110 ⁰C MH18F Angewandte Chemie International accepted for publication 2014

  16. MH18F images bacteria by Micro-CT/PET Relative radio activity 109 EC Control *** 109 CFUs EC Control Angewandte Chemie International accepted for publication 2014

  17. Conclusions Gal Gal Gal Gal Transcription Factor Delivery Imaging Bacteria

  18. Acknowledgments Funding from the NIH

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