|
|
|
Lipid-based carriers. Millions of years of evolution have endowed viruses with the ability to release their genomic cargo within target cells after they have been internalized. Since more than one third of all new drug leads fail due to delivery problems, we are designing delivery strategies that mimic the endosomal uptake and acidification mechanism that these viruses employ. The materials prepared in our lab—including, lipids, lipopolymers, hydrogels, diblock copolymers and polyrotaxanes—are designed to be bioresponsive due to the strategic placement of labile functional groups within their structures. Upon entry into target biological compartments such as acidic endosomes, oxidative phagosomes, or proteolytic environments, these carrier systems undergo degradation, which greatly enhances the bioavailability and efficacy of the cargo within the delivery vehicle.
ReferencesD. H. Thompson, Y. Rui & O. V. Gerasimov, "Triggered Release from Liposomes Mediated by Physically- and Chemically-Induced Phase Transitions" Surfactant Science Series: Vesicles, M. Rosoff, Ed.; Marcel Dekker: New York, NY, 1996, pp. 679-746. I. Szleifer, O. V. Gerasimov & D. H. Thompson, “Spontaneous Liposome Formation Induced by Grafted Poly(ethylene oxide) Layers: Theoretical Prediction and Experimental Verification” Proceedings of the National Academy of Sciences 1998 95, 1032-1037. N. Wymer, O. V. Gerasimov & D. H. Thompson, “Cascade Liposomal Triggering: Light-Induced Ca2+ Release from Plasmenylcholine Liposomes Triggers PLA2-Catalyzed Hydrolysis and Contents Leakage from DPPC Liposomes” Bioconjugate Chemistry 1998 9, 305-308. Y. Rui, S. Wang, P. S. Low & D. H. Thompson, “Diplasmenylcholine-Folate Liposomes: An Efficient Vehicle for Intracellular Drug Delivery” Journal of the American Chemical Society 1998 120, 11213-11218. M. M. Qualls & D. H. Thompson, “Synergistic Phototoxicity of Chloroaluminum Phthalocyanine Tetrasulfonate Delivered via Acid-Labile Diplasmenylcholine-Folate Liposomes” International Journal of Cancer 2001 93, 384-392. J. A. Boomer, D. H. Thompson & S. Sullivan, “Formation of Plasmid-Based Transfection Complexes with an Acid-Labile Cationic Diplasmenyl Lipid: In Vitro and In Vivo Gene Transfer” Pharmaceutical Research 2002 19, 1289-1298. J. A. Boomer, H. D. Inerowicz, Z.-Y. Zhang, N. Bergstrand, K. Edwards, J.-M. Kim & D. H. Thompson, “Acid-Triggered Release from Sterically-Stabilized Fusogenic Vesicles: A Novel DePEGylation Strategy”, Langmuir 2003 19, 6408-6415. N. Bergstrand, M. C. Arfvidsson, J.-M. Kim, D. H. Thompson & K. Edwards, “Interactions Between pH-Sensitive Liposomes and Model Membranes”, Biophysical Chemistry 2003 104, 361-379. J. Shin & D. H. Thompson, “Direct Synthesis of Plasmalogens from Allyl Substituted Glycerols”, Journal of Organic Chemistry 2003 68, 6760-6766. M. D. Kennedy, K. N. Jallad, D. H. Thompson, P. S. Low & D. Ben-Amotz, “Optical Imaging of Folate-Receptor Positive Tissues and Tumors Targeted with a Folate-Fluorescein Conjugate”, Journal of Biomedical Optics 2003 8, 636-641. V. Dixit, J. Van den Bossche, D. M. Sherman, D. H. Thompson & R. P. Andres, “Synthesis and Grafting of Thioctic Acid-PEG-Folate Conjugates onto Au Nanoparticles for Selective Targeting of Cancer Cells”, Bioconjugate Chemistry 2006 17, 603-609 J. Van den Bossche, J. Shin, D. H. Thompson, “Improved Plasmalogen Synthesis Using Organobarium Intermediates”, Journal of Organic Chemistry 2007 72, 5005-5007. Polyrotaxane carriers. We have also been preparing a wide variety of polyrotaxane materials using a chemoselective approach to blocking only the polymer chain termini of pseudo-polyrotaxanes to retain the threaded CDs and produce stable polyrotaxane constructs. This approach is being used to prepare materials for gene delivery, resorbable hydrogels and drug carriers with programmable drug release rates.
References S. Loethen, T. Ooya, H. S. Choi, N. Yui & D. H. Thompson, “Synthesis, Characterization and pH-Triggered Dethreading of a-Cyclodextrin Polyethylene Glycol Polyrotaxanes Bearing Cleavable Stoppers”, Biomacromolecules 2006 7, 2501-2506. T. Ooya, D. Inoue, H. S. Choi, Y. Kobayashi, S. Loethen, D. H. Thompson, Y. Ho Ko, K. Kim & N. Yui, “pH-Responsive Movement of Cucurbit[7]uril in a Dual Polypseudorotaxane: Contribution of Dimethyl b-Cyclodextrin”, Organic Letters 2006 8, 3159-3162. S. Loethen, J.-M. Kim, D. H. Thompson, “Biomedical Applications of Cyclodextrin-Based Polyrotaxanes”, Journal of Macromolecular Science C-Polymer Reviews 2007 47, in press.
Polymer Hydrogels: Transglutaminase enzymes are ubiquitous Ca2+-dependent enzymes which catalyze the formation of crosslinks between glutamine and lysine resides of proteins. Extensive transglutaminase-mediated crosslinking of soluble proteins is believed to be responsible for rapid physical gelation of certain biological fluids. A common biological strategy for regulating the activity of transglutaminase enzymes is control of intracellular and extracellular Ca2+ concentration, mediated by lipid bilayer membranes. Stimuli-responsive synthetic lipid vesicles offer a unique opportunity to regulate transglutaminase-mediated gelation by sequestering and then releasing enzyme-activating ion such as Ca2+. Ca2+ release from light sensitive liposomes can be used to trigger TG-mediated crosslinking of proteins to form hydrogels suitable for the purpose of wound healing, drug delivery, and tissue engineering. Natural proteins and synthetic polypeptides determined to be transglutaminase substrates are under investigation, in combination with Factor XIII and tissue transglutaminase, to formulate solutions which undergo rapid gelation upon activation of the enzyme by exposure to Ca2+.
References J. H. Collier, B.-H. Hu, J. W. Ruberti, Z.-Y. Zhang, P. Shum, D. H. Thompson & P. B. Messersmith, “Thermally and Photochemically Triggered Self-Assembly of Peptide Hydrogels” Journal of the American Chemical Society 2001 123, 9463-9464. Z.-Y. Zhang, P. Shum, M. Yates, P. B. Messersmith & D. H. Thompson, “Formation of Fibrinogen-Based Hydrogels Using Phototriggerable Diplasmalogen Liposomes” Bioconjugate Chemistry 2002 13, 640-646. |
