The Oupicky Lab focuses on the broad field of drug delivery and nanomedicine, with emphasis on delivery of therapeutic nucleic acids and drug/nucleic acid combinations. Our research promises to enable or significantly improve a range of therapeutic approaches investigated in the field of nanomedicine. The research in our lab is highly interdisciplinary and covers all development aspects of delivery systems, including synthesis of novel polymers and nanomaterials, evaluation of the delivery activity in vitro and studies of the pharmacokinetics and activity of the delivery vectors in vivo in disease models. We put emphasis on a synthesis of new materials and on understanding the physicochemical properties of delivery systems and their interactions with living systems. Currently active research projects focus on development of nanomedicines for delivery of various combinations of therapeutic agents, including drug-gene, drug-siRNA, drug-miRNA and drug-drug combinations.
Polymeric CXCR4 antagonists (PCX) as dual-function nucleic acid delivery vectors
Synthetic polycations have been investigated widely as delivery vectors of nucleic acid therapeutics, such as plasmid DNA and siRNA. Polycations form complexes, called polyplexes, with the nucleic acids, thereby protecting them from degradation and facilitating transport across cellular membranes. Traditionally, polycations have been viewed as pharmacologically inert components of the delivery systems. We proposed a conceptually new approach that polycations can have both a delivery function as well as pharmacologic activity, to enhance the therapeutic outcome of gene and siRNA therapies. We developed a novel class of polycations that not only deliver nucleic acids but also function as antagonists of the CXCR4 chemokine receptor. Many preclinical and clinical studies have found significant correlation between CXCR4 overexpression and tumor growth and metastasis in many different types of cancer. CXCR4 expression is often associated with poor survival and aggressive type of cancer. We are working on developing our polycations into biodegradable nanocarriers that function dually as antimetastatic agents due to their CXCR4-inhibiting ability and as delivery vectors of therapeutic genes or siRNA targeting genes crucial in cancer progression. We predict that this approach will have significant impact and lead to major advancements in the treatment of metastatic cancer. In addition to application in cancer, we are developing PCX for applications in inflammatory disorders such as inflammatory bowel disease and psoriasis.
- J. Li, Y. Zhu, S. Hazeldine, C. Li, D. Oupicky. “Dual-function CXCR4 Antagonist Polyplexes to Deliver Gene Therapy and Inhibit Cancer Cell Invasion.” Angewandte Chemie, Int. Ed., 2012, 51(35):8740-3. (Abstract)
- J. Li, D. Oupicky. “Effect of Biodegradability on CXCR4 Antagonism, Transfection Efficacy and Antimetastatic Activity of Polymeric Plerixafor.” Biomaterials, 2014, 35(21):5572-9. (Abstract)
- J. Li, A. M. Lepadatu, Y. Zhu, M. Ciobanu, Y. Wang, S. C. Asaftei, D. Oupicky. “Examination of Structure-activity Relationship of Viologen-Based Dendrimers as CXCR4 Antagonists and Gene Carriers.” Bioconjugate Chemistry, 2014, 25(5):907-17. (Abstract)
- Y. Wang, J. Li, D. Oupicky. “Polymeric Plerixafor: Effect of PEGylation on CXCR4 Antagonism, Cancer Cell Invasion, and DNA Transfection.” Pharmaceutical Research, 2014, 31(12):3538-48. (Abstract)
Polycationic prodrugs that target dysregulated polyamine metabolism in cancer
Progress in the development of non-viral gene delivery vectors continues to be hampered by their low transfection activity and toxicity of the cationic molecules. One way to overcome the low transfection is to combine the therapeutic gene with traditional small-molecule drugs to enhance the overall therapeutic activity. Such drug/gene combination therapies can be achieved by a simple combination of gene therapy protocols with existing drugs. Alternatively, synthetic gene delivery vectors can be designed that not only deliver a gene but also augment the activity of the gene by exerting their own pharmacologic effect. We are developing cationic prodrugs based on a class of drugs called polyamine analogs that can be used for gene delivery. Polyamine analogs exploit the self-regulatory nature of the metabolism of cellular polyamines and have multiple targets in the polyamine pathway. Polyamine metabolism is frequently dysregulated in cancer and other hyper-proliferative diseases. We are exploring various self-immolative linker chemistries to synthesize polycationic prodrugs based on polyamine analogues such as bisethylnorspermine (BENSpm).
- Y. Dong, J. Li, C. Wu, D. Oupicky. “Bisethylnorspermine Lipopolyamine as Potential Delivery Vector for Combination Drug/Gene Anticancer Therapies.” Pharmaceutical Research, 2010, 27(9), 1927-38. (Abstract)
- Y. Dong, Y. Zhu, J. Li, Q. Zhou, C. Wu, D. Oupicky. “Synthesis of Bisethylnorspermine Lipid Prodrug as Gene Delivery Vector Targeting Polyamine Metabolism in Breast Cancer.” Molecular Pharmaceutics, 2012, 9(6), 1654-64. (Abstract)
- Y. Zhu, J. Li, S. Kanvinde, Z. Lin, S. Hazeldine, R. K. Singh, D. Oupický. “Self-immolative Polycations as Gene Delivery Vectors and Prodrugs Targeting Polyamine Metabolism in Cancer.” 2014, [Epub ahead of print] (Abstract)
Gene delivery controlled by redox potential gradients
Self-assembly complexes of nucleic acids and polycations (polyplexes) are investigated as promising delivery vectors for a variety of nucleic acid therapeutics. One of the several stimuli, which has been utilized for improving the efficiency of nucleic acid delivery, is the redox potential gradient existing between extracellular and intracellular environments. The existence of a high redox potential gradient between oxidizing extracellular space and the reducing environment of subcellular organelles has been exploited by incorporating disulfide bonds into the structure of the delivery vectors to provide them with the capability to release the therapeutic nucleic acids selectively in the subcellular reducing space. Our interests range from the synthesis of novel reducible polycations, understanding the mechanism of polyplex disassembly in response to applying the redox stimulus, all the way to understanding the mechanism of decreased toxicity and altered transfection activity of the polyplexes. In addition, we are investigating the possibility of exploiting altered redox cellular states associated with pathological states for improving the activity and selectivity of transfection of redox-responsive polyplexes.
- J. Chen, C. Wu, D. Oupicky. “Bioreducible Hyperbranched Poly(amido amine)s for Gene Delivery.” Biomacromolecules, 2009, 10(10):2921-7. (Abstract)
- D. S. Manickam, J. Li, D. A. Putt, Q. H. Zhou, C. Wu, L. H. Lash, D. Oupicky. “Effect of Innate Glutathione Levels on Activity of Redox-responsive Gene Delivery Vectors.” Journal of Controlled Release, 2010, 141(1), 77-84. (Abstract)
- J. Li, D. S. Manickam, J. Chen, D. Oupicky. “Effect of Cell Membrane Thiols and Reduction-triggered Disassembly on Transfection Activity of Bioreducible Polyplexes.” European Journal of Pharmaceutical Sciences, 2012, 46(3), 173-80. (Abstract)
- C. Wu, J. Li, Y. Zhu, J. Chen, D. Oupicky. “Opposing Influence of Intracellular and Membrane Thiols on the Toxicity of Reducible Polycations.” Biomaterials 2013, 34(34):8843-50. (Abstract)
- D. Oupicky, J. Li. “Bioreducible Polycations in Nucleic Acid Delivery: Past, Present, and Future Trends.” Macromolecular Bioscience, 2014, 14(7):908-22. (Abstract)
Stimulus-controlled drug delivery from mesoporous silica nanoparticles
Mesoporous silica-based nanomaterials have many attractive features for biomedical applications. They include large surface area, tunable pore size, favorable safety profile, and well-defined surface properties available for further functionalization. Because the pores exhibit a relatively narrow size distribution in the range of 2–10 nm, mesoporous silica can selectively host molecules and mixtures of molecules of various sizes, shapes, and functionalities. In principle, the molecules can be released at a later stage, providing an exciting platform for imaging and drug delivery. Significant effort has been devoted to the development of “smart” mesoporous silica nanoparticles, in which uptake and delivery of drugs in the pore voids can be controlled by selectively opening and closing the pores in response to a variety of stimuli. We are working on developing porous silica nanoparticles for delivery of siRNA/drug combinations to treat metastatic breast cancer.
- Y. You, K. Kalebaila, S. L. Brock, D. Oupicky. “Temperature-controlled Uptake and Release in PNIPAM-modified Porous Silica Nanoparticles.” Chemistry of Materials, 2008, 20, 3354-9. (Abstract)
- S. R. Bhattarai, E. Muthuswamy, A. Wani, M. Brichacek, A. L. Castaneda, S. Brock, D. Oupicky. “Enhanced Gene and siRNA Delivery by Polycation-modified Mesoporous Silica Nanoparticles Loaded with Chloroquine.” Pharmaceutical Research, 2010, 27(12), 2556-68. (Abstract)
- A. Wani, E. Muthuswamy, G. H. Savithra, G. Mao, S. Brock, D. Oupicky. “Surface Functionalization of Mesoporous Silica Nanoparticles Controls Loading and Release Behavior of Mitoxantrone.” Pharmaceutical Research, 2012, 14(7):908-22. (Abstract)