We are a lab driven by crazy ideas and unconventional approaches. We value random discovery, serendipity and the power of observation. At the same time, we are doing systematic studies using a variety of methodologies from serum biochemistry to in vivo pharmacology to population studies in healthy persons and patients. We welcome people who are excited by new discoveries.
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).
Superparamagnetic crystalline iron oxide (SPIO) is a significant magnetic resonance imaging resonance imaging (MRI) contrast agent by itself and as a component of multifunctional nanomedicines for cancer imaging and treatment (over 7000) citations in PubMed). SPIO consist of magnetite (Fe3O4)-maghemite (gamma-Fe2O3)
crystals of 5-10-nm size embedded in a meshwork of polymer dextran. We can make these particles of different sizes, shapes and magnetic properties (Fig 2), from nanoworms to small monocrystalline SPIO.
Funded by NIH R01 grant, we use SPIO in order to decipher the mechanisms of complement activation of nanoparticles, understand the consequences of complement activation systemwide, and to design synthetic strategies to mitigate complement assembly on 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 cancers.
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.
The ability to isolate intact biomarkers and tumor cells with high purity and
efficiency will facilitate clinical management of malignancies and early diagnosis
of asymptomatic cancers. Funded by an NIH R33 grant, we are developing novel technologies for isolation and enrichment of 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). Recently, we performed a limited clinical study and isolated CTCs, CTC clusters and (excitingly) 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.