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Research Interests
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Our main research focus is to design, develop and evaluate novel nanomaterials and nanoarchitectures for cancer molecular imaging and targeted therapeutic applications. Two design principles are emphasized throughout research: (1) understand tumor pathophysiology and identify key cancer targets to improve biological specificity, and (2) build innovative nanomedicine platforms with non-linear bioresponsive properties to achieve diagnostic and therapeutic efficacy.

1. "ON/OFF" Imaging Nanoprobes

Advances in cancer biology and biochemistry have rapidly produced many exploitable molecular targets (e.g. EGFR) and corresponding target-specific ligands (e.g. peptides/peptoids, mAbs, RNA aptamers) for personalized diagnosis and therapy of cancer. Their implementation in cancer molecular imaging, however, is greatly limited due to the always ON signal output from most current contrast probes (e.g. small molecular dyes, QD). For example, humanized mAbs have long blood circulation times. Conjugation with an always ON probe leads to persistent fluorescence in blood and a reduction in image contrast between tumor/normal tissues.

fig1One new research direction in our lab is to design and develop imaging nanoprobes with ON/OFF activatable mechanisms that can respond to pathophysiological signals (e.g. pH). Such nanoprobes will stay "silent" during blood circulation, but can be turned ON in response to cancer signals (e.g. acidic tumor pH, receptor-mediated uptake). One example is the development of a series of tunable, pH-activatable fluorescent nanoprobes (Angew. Chem. 2011). They have shown a fast response (<5 ms), up to 55-fold increase of emission intensity between OFF and ON states, and only require <0.25 pH unit for activation (vs. 2 pH unit for small molecular dyes). All the nanoprobes are not fluorescent at pH 7.4, but can be activated at tunable pH values in the physiological range (5.0-7.4). Nanoparticles with different transition pH can be selectively activated in specific endocytic compartments such as early endosomes (pH 5.9-6.2) or lysosomes (5.0-5.5). This capability allows for the development of organelle-specific imaging probes or drug carriers for cancer diagnosis or therapy, respectively. pH-activatable nanoprobes are currently being investigated to target tumor vasculature and head/neck cancer cells for image-guided resection of tumors.

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22. Ultra-Sensitive MRI Nanoprobes

Magnetic resonance imaging (MRI) is a powerful clinical imaging technique that allows for non-invasive tomographic visualization of anatomic structures with high spatial resolution and soft tissue contrast. However, its application in molecular imaging of cancer has been limited by the lack of sensitivity and detection accuracy in depicting the biochemical expression of these diseases.

To overcome these limitations, we recently established an ultra-sensitive design of superparamagnetic polymeric micelles (SPPM) and an off-resonance saturation (ORS) method to enhance the imaging efficacy of tumor biomarkers in vivo. In the SPPM design, clustering of iron oxide nanoparticles inside the micelle core dramatically increased the T2 relaxivity (>10 times) on a per Fe basis over single SPIO micelles (Adv. Mater. 2005). SPPM nanoparticles encoded with c(RGDfK) were able to target the alpha(v)beta(3)-expressing microvasculature in A549 non-small cell lung tumor xenografts in mice (Cancer Res. 2009). In addition to SPIO, other MR probes (e.g. T1, CEST, and hyperpolarization) are also being considered with a potential synergy that can lead to non-linear increase in imaging output.

New directions in this area include the implementation of activatable mechanisms as described in the previous section into the MR nanoprobe design. Multi-chromatic nanoprobes are also being developed and conjugated with different lung cancer-targeting peptides from phage screening to diagnose phenotypic expressions of lung cancer.

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Theranostic nanomedicine3. Theranostic Nanomedicine

Multifunctional nanomedicine with integrated imaging and therapeutic functions have received considerable attention for image-guided therapy of cancer. Compared with small molecular-based contrast agents or therapeutic drugs, this new nanomedicine paradigm holds considerable promise that allows for the molecular diagnosis of disease, simultaneous monitoring and treatment, and targeted therapy with minimal toxicity.

Our research interests in this area involve the development of multifunctional micelles that incorporate cancer-targeting, MR imaging sensitivity, and drug delivery functions (Nano Lett. 2006; Mol. Pharm. 2010). More recently, we are focusing on a new drug, beta-lapachone, which is bioactivated by an oxidoreductase enzyme, NQO1. NQO1 is highly expressed in a variety of tumors including lung, pancreatic, breast and prostate cancers. Upon NQO1 activation, each drug can consume over 60 mole equivalent of NADPH and produce a large amount of ROS, which leads to DNA damage and PARP-1 hyper-activation. Cell death is independent of cell cycle and p53 status and no drug resistance has been found in cancer cells (PNAS, 2007). Micelle delivery of beta-lapachone has overcome the hemolysis side effect as observed in ARQ501 (a clinical formulation using cyclodextrin) while leading to increased antitumor efficacy (Cancer Res. 2010). Current research focuses on the synergy between SPIO and beta-lapachone in tumor treatment and development of prodrug micelles with pH-sensitive release of the drug.

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