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

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Presentation on theme: "In vivo delivery of transcription factors with multifunctional oligonucleotides Murthy Laboratory U.C. Berkeley Department of Bioengineering."— Presentation transcript:

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

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

5 DARTs undergo pH sensitive hydrolysis

6 DARTs are pH sensitive membrane disruptive agents

7 DARTs can deliver Nrf2 to cells Nrf2DART-Nrf2

8 HO1 NQO1 GCLC GAPDH Control Free Nrf2DART-Nrf2 DARTs can deliver Nrf2 to hepatocytes and transcribe downstream genes

9 DARTs are designed to deliver Nrf2 and treat liver disease

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

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

12 Maltodextrin Transporter The maltodextrin transporter is an ideal target for imaging bacteria MDPs Ning et al. Nature Materials 2011, 10(8), 602-607.

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

14 p s -1 cm -2 10 7 EC Saline 10 7 ECSaline * MDPs can image bacteria in vivo MDP-2 Ning et al. Nature Materials 2011, 10(8), 602- 607.

15 CuI, DIPEA, DMF, rt 1.K 18 F, CH 3 CN, 110 ⁰C; 2.NaOH, H 2 O, 110 ⁰C MH 18 F Maltohexaose- 18 F (MH 18 F) for PET imaging Angewandte Chemie International accepted for publication 2014

16 MH 18 F images bacteria by Micro- CT/PET 10 9 EC Control 10 9 CFUs ECControl *** Relative radio activity Angewandte Chemie International accepted for publication 2014

17 Conclusions Imaging Bacteria Transcription Factor Delivery Gal

18 Acknowledgments Funding from the NIH

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