Please click “Specific examples” for more detailed information on each topic.

Two major hurdles in cancer therapy are early detection of tumor in the body and efficient delivery of drugs to the tumor cell target. The use of contrast agents modified to recognize unique and over-expressed markers on tumor cell surface shows a great potential in cancer diagnostics. My group is developing various targeting strategies against growth factor receptors (EGFR, Her2, ephrin B2), growth factors (EGF, VEGF), cell adhesion molecules (integrins, Muc1), protease (MMP), and hormone receptor (TSHR). Delivery platform is built on liposomes, polymer, and magnetic nanoparticles with their surface modified for the conjugation of antibodies and peptides for target recognition. The choice of specific nanoplatforms are based on the type of payload ferried by the nanoparticles and imaging modality such as magnetic resonance imaging (MRI), optical whole body imaging (near-infrared fluorescence dye, bio-lumininescence), and computed tomography (CT). For instance, nanoparticles containing superparamagnetic iron oxide are suitable for MRI while those with iodines are for CT. Liposomes and recently developed amphiphilic polymer nanoparticles called urethane acrylate nonionomer (UAN) are designed to deliver nucleic acids (DNA, siRNA, microRNA) and small molecule drug compounds. Multi-scale approach is critical to developing effective diagnostic and therapeutic nanoplatforms, requiring expertise in molecular engineering, material design, cell biology, animal models, and imaging. Specific examples of Project I

Inflammation is a protective response by the host to remove the injurious stimuli from pathogen as well as to initiate the healing process. Increasing evidence now suggests that inflammation underlies the etiology of cardiovascular disease, where inflamed leukocyte such as monocytes and macrophages infiltrate into arterial intima, accumulate lipoprotein particles, and release pro-inflammatory cytokines and matrix metalloproteinases that can damage vasculature structure and lead to atherosclerotic lesion. The pathological role of inflammation is also being recognized as a critical component of tumor progression and metastasis. Neoplastic cells express cytokines such as interleukin (IL)-6 and colony-stimulating factor (CSF) that recruit macrophages (called tumor-associated macrophages), which in turn produce potent angiogenic and lymphagiogenic growth factors and cytokines, all of which are soluble factors that potentiate tumor progression. Despite a critical need in early, accurate detection of inflammation and the delivery of therapeutics into the inflamed vasculature, effective diagnostic and therapeutic tools have yet to be developed. The central idea is that nanoparticles designed for imaging and drug delivery and functionalized with the molecules targeting ICAM-1 can be developed into in vivo detection and drug delivery toward inflammation. Such nanoplatforms should produce a wide-ranging impact on broad spectrum of biomedicine, particularly on diagnosis and treatment of cardiovascular disease and cancer. By combining recently developed nanoparticles, LFA-1 I domain, and a mouse model of inflammation, we will achieve optimization of nanoparticles for maximum specificity and minimization of off-target effects, development of quantitative MRI to study bio-distribution of nanoparticles, and validation of the therapeutic benefit of anti-inflammatory agent delivered into inflamed site. Specific examples of Project II

Adeno-associated virus (AAV) is a non-pathogenic virus and has been extensively studied as a gene therapy vector in transduction of neuronal, cervical, breast, prostate, and colon cells and tumor cell lines. Clinical trials on AAV-mediated gene delivery to treat Parkinson’s disease have shown a great promise, spurring interest in a potential use of AAV to treat many debilitating neurological diseases. Due to the specialized brain vasculature structure called the blood brain barrier (BBB), gene therapy vectors need to be delivered directly to the brain by an invasive surgery. Although the BBB prevents macromolecules in the vasculature from entering into the brain, a number of receptors (e.g., transferrin receptor, acetylcholine receptors, etc.) on the brain endothelium actively transport the molecules into the brain. We hypothesize that AAV with its capsid protein modified to elicit receptor-mediated transcytosis may enable intravenously injected AAV to distribute globally in the brain. Specific examples of Project III