Translational Bio-Nanosciences Laboratory: Dmitri Simberg, PhD

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.

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.

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.

Relevant publications

1. 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.
2. 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.
3. Wang, G.; Inturi, S.; Serkova, N. J.; Merkulov, S.; McCrae, K.; Russek, S. E.; Banda, N. K.; Simberg, D. (2014) High-Relaxiv​ity Superparamagnetic Iron Oxide Nanoworms with Decreased Immune Recognition and Long-Circulating Properties. ACS Nano, 8, 12437-49.
4. 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.

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.

Relevant Publications

1. 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.
2. 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.
3. 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.

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.

Relevant Publications

1. 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.
2. 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.
3. Li, Y.; Lofchy, L.; Wang, G.; Gaikwad, H.; Fujita, M.; Simberg, D. Pegylated Liposomes Accumulate in the Areas Relevant to Skin Toxicities Via Passive Extravasation across "Leaky" Endothelium. ACS Nano 2022, 10.1021/acsnano.2c00423,
4. Wang, G.; Zannikou, M.; Lofchy, L.; Li, Y.; Gaikwad, H.; Balyasnikova, I. V.; Simberg, D. Liposomal Extravasation and Accumulation in Tumors as Studied by Fluorescence Microscopy and Imaging Depend on the Fluorescent Label. ACS Nano 2021, 10.1021/acsnano.1c02982,