We value random discovery, serendipity, and power of observation. At the same time, we pursue systematic studies using a variety of methodologies, from serum biochemistry, to in vivo pharmacology to population studies in healthy persons and in patients. We are always looking for enthusiastic and energetic individuals.
Project 1: Interaction between immune system and nanocarriers
Intravenously injected nanomaterials undergo interactions with plasma components and immune receptors, with subsequent clearance by body macrophages and monocytes. This process is the major problem in nanomedicine since it decreases the dose of nanoparticles in the tumor, limits the efficiency of imaging and therapy, and causes toxicity. There is still insufficient knowledge of the basic mechanisms that lead to nanoparticle recognition and elimination.
SPIO is the only T2/T2* magnetic resonance imaging (MRI) contrast agent used in clinic. (SPIO consists of magnetite (Fe3O4)-maghemite (gamma-Fe2O3) crystals of 5–10-nm size embedded in a meshwork of polymer dextran. We make these particles in different sizes, shapes, and magnetic properties from nanoworms to small monocrystalline SPIO.
Funded by NIH R01 grant, we use SPIO in order to decipher the mechanisms of immune activation by nanoparticles, understand the consequences of complement activation, and to design synthetic strategies to mitigate complement activation by nanoparticles. Recently we described in Nature Nanotechnology the mechanisms by which nanoworms activate complement via the alternative pathway. We are using biomimetic and synthetic approaches to design safe and efficient imaging and drug delivery carriers based on nanoworms for therapy and imaging of diseases.
- Simberg, D., Park, J. H., Karmali, P. P., Zhang, W. M., Merkulov, S., McCrae, K., Bhatia, S. N., Sailor, M., and Ruoslahti, E. (2009) Differential proteomics analysis of the surface heterogeneity of dextran iron oxide nanoparticles and the implications for their in vivo clearance. Biomaterials 30, 3926-3933.
- Chao, Y., Karmali, P. P., Mukthavaram, R., Kesari, S., Kouznetsova, V. L., Tsigelny, I. F., and Simberg, D. (2013) Direct recognition of superparamagnetic nanocrystals by macrophage scavenger receptor SR-AI. ACS Nano 7, 4289-4298.
- Wang, G.; Inturi, S.; Serkova, N. J.; Merkulov, S.; McCrae, K.; Russek, S. E.; Banda, N. K.; Simberg, D. (2014) High-Relaxivity Superparamagnetic Iron Oxide Nanoworms with Decreased Immune Recognition and Long-Circulating Properties. ACS Nano, 8, 12437-49.
- Chen, F.; Wang, G.; Griffin, J. I.; Brenneman, B.; Banda, N. K.; Holers, V. M.; Backos, D. S.; Wu, L.; Moghimi, S. M.; Simberg, D., Complement Proteins Bind to Nanoparticle Protein Corona and Undergo Dynamic Exchange in Vivo. Nature nanotechnology 2017, 12, 387-393.
Project 2: Painted red blood cells as long-circulating carriers for leukemia therapy
Red blood cells (RBCs) are natural carriers that can deform and squeeze through capillaries, and the immune system does not readily recognize them as foreign. The unique potential of RBCs due to long half-life, biocompatibility, and large volume capacity has not been fully exploited in diagnostics and therapy.
We work on RBC surface chemistry to stably incorporate molecules and ligands on the RBC surface and demonstrated their biocompatibility and targeting in vitro and in vivo. Funded by NIH R01 grant, we are currently working on loading drugs into RBCs membrane and the design of painted RBCs for targeting leukemia cells, in particular, the most common adult leukemia called AML.
- Shi, G., Mukthavaram, R., Kesari, S., and Simberg, D. (2014) Distearoyl anchor-painted erythrocytes with prolonged ligand retention and circulation properties in vivo. Advanced healthcare materials 3, 142-148.
- Mukthavaram, R.; Shi, G.; Kesari, S.; Simberg, D. (2014) Targeting and Depletion of Circulating Leukocytes and Cancer Cells by Lipophilic Antibody-Modified Erythrocytes. Journal of Controlled Release 183, 146-53.
- Smith, W. J.; Tran, H.; Griffin, J. I.; Jones, J.; Vu, V. P.; Nilewski, L.; Gianneschi, N.; Simberg, D., Lipophilic Indocarbocyanine Conjugates for Efficient Incorporation of Enzymes, Antibodies and Small Molecules into Biological Membranes. Biomaterials 2018, 161, 57-68.
Project 3: Mechanisms of accumulation of drug carriers in tissues including skin
Skin is one of the largest organs in the body and the site of many diseases. Using near-infrared spectroscopy and intravital microscopy, we recently observed that systemically injected liposomes bind to the blood vessels, cross them and accumulate in cells outside of blood vessels. The same phenomenon is also observed for clinically used liposome Doxil. We are working to understand this phenomenon and to exploit it for the delivery of drugs to the skin.
- Griffin JI, Benchimol MJ, and Simberg D. Longitudinal monitoring of skin accumulation of nanocarriers and biologicals with fiber optic near-infrared fluorescence spectroscopy (FONIRS). J Control Release 2017, 247, 167-174.
- Griffin, J. I.; Wang, G.; Smith, W. J.; Vu, V. P.; Scheinman, R.; Stitch, D.; Moldovan, R.; Moghimi, S. M.; Simberg, D., Revealing Dynamics of Accumulation of Systemically Injected Liposomes in the Skin by Intravital Microscopy. ACS Nano 2017, 11, 11584-11593.
Project 4: In vitro cancer diagnostics and monitoring using gas microbubbles
Biomarkers such as circulating tumor cells (CTCs), exosomes and DNA could be isolated from biological fluids and analyzed for the diagnosis and prognosis of cancer. Ability to isolate intact biomarkers and tumor cells with high purity and efficiency will facilitate clinical management of malignancies and early diagnostics of asymptomatic cancers. Funded by NIH R33 grant, we are developing novel technologies for isolation and enrichment or rare tumor markers from biological fluids. In particular, for isolation of circulating tumor cells (CTCs), we developed buoyant perfluorocarbon microbubbles coated with various targeting antibodies. Microbubbles efficiently target tumor cells in whole blood and isolate the cells after a quick centrifugation step with high purity. Recently we performed a limited clinical study and isolated CTCs, CTC clusters and tumor-derived microparticles from the blood of cancer patients. Our goal is to perform genetic analysis of the material isolated from patients as well as specific staining of receptor status in the isolated cells and in microparticles.
- Simberg D and Mattrey R. Targeting of perfluorocarbon microbubbles to selective populations of circulating blood cells. J Drug Targeting 2009, 17(5): 392-398.
- Shi, G., Cui, W., Benchimol, M., Liu, Y. T., Mattrey, R. F., Mukthavaram, R., Kesari, S., Esener, S. C., and Simberg, D. (2013) Isolation of rare tumor cells from blood cells with buoyant immuno-microbubbles. Plos One 8, e58017
- Shi, G.; Cui, W.; Mukthavaram, R.; Liu, Y. T.; Simberg, D. (2013) Binding and isolation of tumor cells in biological media with perfluorocarbon microbubbles. Methods, 64, 102-7.
- Wang, G.; Benasutti, H.; Jones, J. F.; Shi, G.; Benchimol, M.; Pingle, S.; Kesari, S.; Yeh, Y.; Hsieh, L. E.; Liu, Y. T.; Elias, A.; Simberg, D., Isolation of Breast Cancer CTCs with Multitargeted Buoyant Immunomicrobubbles. Colloids Surf B Biointerfaces 2018, 161, 200-209