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University of Colorado Denver

 

Translational Bio-Nanosciences Laboratory

Research


Research Interests

We are interested in interactions between the immune system and nanomaterials. Immune system recognizes and clears nanoparticles from the body just like any other foreign pathogen. Bio/nano interactions have clinically important outcomes (for example clearance of drug delivery systems by liver and spleen, or hypersensitivity upon injection). Our goal is to understand the principles by which immune system recognizes the surface in order to design long circulating, safe and efficient drug delivery and imaging nanomedicines. Our favorite type of material is superparamagnetic iron oxide nanoworms, which are a promising biomedical agent and MRI contrast agent. Our additional focus is use of red blood cells (RBCs), the most abundant and available cell type in the body, for delivery of drugs and biologicals to leukemia cells. Lastly, we are interested in using buoyant gas microbubbles in order to isolate rare tumor cells and biomarkers form blood for highly sensitive detection of cancer.

Specific Projects

Project 1: Interaction between complement system and nanocarriers

Intravenously injected nanomaterials undergo interactions with plasma components and cell 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. Complement system is a critical part of serum innate immunity that comprises about 5% of globulins and is responsible for eliminating and destroying pathogens. Activation of complement results in formation of membrane pore complex C5b-C9 and release of extremely potent anaphylatoxins C3a and C5a.1 Opsonization of pathogens by C3b and its cleaved forms (e.g., iC3b, C3d) triggers immune recognition by neutrophils, eosinophils, lymphocytes, monocytes, red blood cells and macrophages. Complement activation is arguably the most serious complication associated with infusion of clinically approved nanoformulations. There is still insufficient knowledge of the basic mechanisms that lead to nanoparticle recognition and elimination via complement. The consequences of complement activation and recognition of nanocarriers loaded with potent chemotherapy by the immune cells could be very broad and yet unknown (Fig. 1).




Project 2: Engineered 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 optimized RBC surface chemistry to stably incorporate molecules and ligands on the RBC surface and demonstrated their excellent biocompatibility and targeting in vitro and in vivo (Fig. 2). We are currently working on loading various chemotherapeutic drugs into RBCs. Funded by NIH R01 grant we are working on the use of targeted RBCs for scavenging leukemia cells, in particular the most common adult leukemia called AML.



Project 3: In vitro cancer diangostics 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 (Fig. 3).

The goal is to develop and test biomarker isolation strategies to enable molecular analysis of patients’ samples for personalized molecular diagnostics and early detection.