Research Associate Professor
Office: Foege N510E
We are inventing the future of medicine by developing powerful new delivery technologies that will for the first time enable the realization of therapies based on intracellularly active biologic drugs. These agents have the potential to revolutionize the treatment of serious diseases such as cancer and antibiotic resistant bacteria while minimizing harmful side effects.
Targeted Drug Delivery
Biologic Drug Delivery
Overcoming antibiotic resistance
Controlled Radical Polymerization
Our research is focused on development of powerful new delivery technologies that will allow for the creation of biomacromolecular therapies with unprecedented therapeutic activity and minimal deleterious side affects. Currently all proteins and peptide drugs target extracellular receptors because of the difficulty of intracellular delivery. The intracellular target universe is rich in disease application space, and many proteins/peptides are known to agonize or antagonize key intracellular targets connected with a corresponding wide variety of specific disease etiologies. Viable drug delivery systems must integrate numerous modular components with different functional properties into a single well-defined nanoparticle format. These components include a pH-responsive segment that enhances membrane transport selectively in the low pH environment of the endosome, a targeting element that directs uptake into specific cells, and a versatile complexation/conjugation element that allows for spontaneous association with the biologic drug. These individual functional requirements must remain active once integrated together into a total delivery system while maintaining good biocompatibility.
Controlled Radical Polymerization
Controlled radical polymerization (CRP) methodologies methodology, including the versatile reversible addition–fragmentation chain transfer (RAFT) polymerization process, are rapidly moving to the forefront in construction of drug delivery vehicles. RAFT polymerization has allowed for the creation of previously unattainable polymeric architectures to be prepared pharmaceutically relevant conditions. RAFT represents one of the most significant recent advances in synthetic chemistry and its application is revolutionizing a broad range of disciplines from traditional polymer science to biology. This unprecedented synthetic latitude is for the first time allowing for the preparation of water-soluble or amphiphilic architectures with precise dimensions and appropriate functionality for attachment and targeted delivery of diagnostic and therapeutic agents. Because this methodology does not require the use of any toxic metal catalysts it is particularly well suited for use in biotechnology applications. Our research is focused on the application of advanced CRP techniques to address and overcome the barriers to successful intracellular drug delivery.
The major challenge associated with the use of biologic drugs is the need for these agents to be delivered “outside-in” to the cytoplasmic compartment of target cells. Hydrophilic biomacromolecules are unable to penetrate cell membranes and therefore must contain some mechanism of endosomol escape in order to reach the cytosol. Viruses and other pathogenic organisms such as Diptheria that have evolved highly effective delivery systems for getting nucleic acids and proteins to intracellular locations and targets. These vectors mediate endosomal escape by incorporating fusogenic proteins (e.g. hemagglutinin) on their viral coat that undergo a pH-induced conformational change from hydrophilic at physiological pH to hydrophobic in response to the acidic endosomal environment. Based on this biologic design, we have developed synthetic polymers to fascilitate cytosolic delivery of intracellular therapeutics. These materials employ the same bioinspired pH-sensing strategy by incorporating carboxylic acids or tertiary amines as well as hydrophobic alkyl segments throughout the polymer backbone. Under extracellular conditions these materials are in a noninteractive “stealth” conformation, but upon exposure to acidic endosomal compartments the acid base equilibrium is shifted triggering a hydrophilic-hydrophobic conformational change. This transition renders the polymeric materials membrane interactive allowing them to disrupt endosomal membranes.
BS, Polymer Science, University of Southern Mississippi, 2006
D. Roy, G. Y. Berguig, B. Ghosn, D. D. Lane, S. Braswell, P. S. Stayton, and A. J. Convertine, Polymer Chemistry, 2014, 5, 1791–1799.
E. Procko, G. Y. Berguig, B. W. Shen, Y. Song, S. Frayo, A. J. Convertine, D. Margineantu, G. Booth, B. E. Correia, Y. Cheng, W. R. Schief, D. M. Hockenbery, O. W. Press, B. L. Stoddard, P. S. Stayton, and D. Baker, Cell, 2014, 157, 1644–1656.
M. C. Palanca-Wessels, A. J. Convertine, R. Cutler-Strom, G. C. Booth, F. Lee, G. Y. Berguig, P. S. Stayton, and O. W. Press, Mol. Ther., 2011, 19, 1529–1537.
A. J. Convertine, D. S. W. Benoit, C. L. Duvall, A. S. Hoffman, and P. S. Stayton, Journal of Controlled Release, 2009, 133, 221–229.
A. J. Convertine, C. Diab, M. Prieve, A. Paschal, A. S. Hoffman, P. H. Johnson, and P. S. Stayton, Biomacromolecules, 2010, 11, 2904–2911.
J. T. Wilson, S. Keller, M. J. Manganiello, C. Cheng, C.-C. Lee, C. Opara, Anthony J Convertine, and P. S. Stayton, ACSNANO, 2013, 7, 3912–3925.