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
Project 1: Interaction between complement
system and nanocarriers
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
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.