MOLECULAR TRANSPORTERS FOR DRUG DELIVERY and diagnostics comprise one of the most exciting areas at the interface of chemistry, biology, and medicine. Our group is involved in numerous collaborations, including work with Stanford Medical School and with biotech companies (one co-founded based on this work). We are pursuing a broad new technology that offers the potential to deliver drugs to cells that would otherwise not enter or do so poorly. Efforts have been expanded to the delivery of peptides, proteins, nucleic acids and even plasmid DNA. Our studies in drug delivery research involve synthesis, computer design, NMR solution structure analysis, bioassay and in vivo investigation. Continuing advances have potential application in the treatment of cancer, AIDS, cardiovascular disease and other disorders; exciting potential also exists for use of delivery technology in gene and antisense therapy. Recent progress in our group highlights the utility of "releasable" conjugates, wherein a drug or probe is attached to the transporter via a chemical linker designed to be cleaved under specific biochemical conditions.
Delivery of Fluorescein into Cells: Fluorescence Microscopy of Fluorescein Conjugates
fluorescein conjugated
to HIV-1 Tat49-57
(our lead from nature)
|
 |
fluorescein conjugated
to an oligomer of
D-Arginine
(a designed superior transporter) |
Releasable Conjugates for Transmembrane Delivery and Real-Time Imaging
Lead references:
- Dubikovskaya, E.A.; Thorne, S.H.; Pillow, T.H.; Contag, C.H.; Wender, P.A., "Overcoming Multidrug Resistance of Small-Molecule Therapeutics with Releasable Octaarginine Transporters." Proc. Natl. Acad. Sci. USA 2008, 105, 12128.
- Lee, H.L.; Dubikovskaya, E.A.; Hwang, H.; Semyonov, A.N.; Wang, H.; Jones, L.R.; Tweig, R.J.; Moerner, W.E.; Wender, P.A. "Single-Molecule Motions of Oligoarginine Conjugates on the Plasma Membrane of Chinese Hamster Ovary Cells." J. Am. Chem. Soc. USA 2008, 130, 9364.
- Wender, P.; Galliher, W.; Goun, E.; Jones, L.; Pillow, T. “The Design of Guanidinium-rich Transporters and Their Internalization Mechanisms” Adv. Drug Delivery Rev. 2008, 60, 452.
- Paul A. Wender, Jung-Min Kee, and Jeffrey M. Warrington, "Practical Synthesis of Prostratin, DPP, and their Analog, Adjuvant Against Latent HIV", Science, 2008, 320, 649-652.
- Wender, Paul A.; Elena A. Goun, Lisa R. Jones, Thomas H. Pillow, Jonathan B. Rothbard, Rajesh Shinde, and Christopher H. Contag “Real-time Analysis of Uptake and Bioactivatable Cleavage of Luciferin-Transporter Conjugates in Transgenic Reporter Mice” Proc. Natl. Acad. Sci. USA 2007, 104, 10340-10345.
- Goun, E. A.; Pillow, T. H.; Jones, L. R.; Rothbard, J. B.; Wender, P. A. "Molecular Transporters: Synthesis of Oligoguanidinium Transporters and Their Application to Drug Delivery and Real-Time Imaging" ChemBioChem 2006, 7, 1497-1515.
- Jones, L. R.; Goun, E. A.; Shinde, R.; Rothbard, J. B.; Contag, C. H.; Wender, P. A. "Releasable Luciferin-Transporter Conjugates: Tools for the Real-Time Analysis of Cellular Uptake and Release" J. Am. Chem. Soc. 2006, 128, 6526-6527.
- Goun, E. A.; Shinde, R.; Dehnert, K. W.; Adams-Bond, A.; Wender, P. A.; Contag, C. H.; Franc, B. L. "Intracellular Cargo Delivery by an Octaarginine Transporter Adapted to Target Prostate Cancer Cells Through Cell Surface Protease Activation" Bioconjugate Chemistry 2006, 17, 787-796.
- Wender, P. A.; Kreider, E.; Pelkey, E. T.; Rothbard, J.; VanDeusen, C. L. "Dendrimeric Molecular Transporters: Synthesis and Evaluation of Tunable Polyguanidino Dendrimers that Facilitate Cellular Uptake" Org. Lett. 2005, 7, 4815-4818.
- Rothbard, J. B.; Jessop, T. C.; Wender, P. A. "Adaptive Translocation: The Role of Hydrogen Bonding and Membrane Potential in the Uptake of Guanidinium-rich Transporters into Cells" Adv. Drug Delivery Rev. 2005, 57, 495-504.
- Kam, NWS; Jessop, TC; Wender, PA; Dai, HJ “Nanotube molecular transporters: Internalization of carbon nanotube-protein conjugates into mammalian cells” J. Am. Chem. Soc. 2004, 6850.
- Rothbard, JB; Jessop, TC; Lewis, RS; Murray, BA; Wender, PA “Role of membrane potential and hydrogen bonding in the mechanism of translocation of guanidinium-rich peptides into cells” J. Am. Chem. Soc. 2004, 9506.
- Wender, P. A.; Rothbard, J. B.; Jessop, T. C.; Kreider, E. L.; Wylie, B. L. "Oligocarbamate Molecular Transporters: Design, Synthesis, and Biological Evaluation of a New Class of Transporters for Drug Delivery" J. Am. Chem. Soc. 2002, 13382.
- Wender, P. A.; Mitchell, D. J.; Pattabiraman, K.; Pelkey, E.; Steinman, L.; Rothbard, J. B. "Molecular Transporters: The Design, Synthesis, and Evaluation of Molecules that Enable or Enhance Cellular Uptake" Proc. Natl. Acad. Sci. USA , 2000, 97, 13003.
- Jonathan B. Rothbard, Sarah Garlington, Qun Lin, Thorsten Kirschberg, Erik Kreider, P. Leo McGrane, Paul A. Wender and Paul A. Khavari, Conjugation of Arginine Oligomers to Cyclosporin A Facilitates Topical Delivery and Inhibition of Inflammation, Nature Medicine 2000, 6, 1253-1257.
