Drug Delivery, Molecular Imaging and Image guided Therapy
Drug delivery research may involve the design of new drugs, or developing strategies to monitor and improve drug transport to target tissue. The primary research focus in this lab is the development of tissue or cell specific contrast agents and probes (both optical and radioactive) for noninvasive molecular imaging of cellular and tissue characterization, for monitoring toxicity, for tracking the biodistribution of known toxins and drugs, and image guided therapy. Another focus is the development of multimodal drugs that simultaneously image and provide therapy. Of primary concern as new drugs are developed is that these drugs be specific in terms of their mechanism and site of action. Verifying that the drug has reached their target is an important component of therapy.
Molecular Imaging allows visualization of not only organs and cells but also biochemical processes within the cells that are associated with specific disease. This information can improve the accuracy of a diagnosis, provide better assessment of the severity of disease and even monitor the response to therapy. Light at the near-infrared wavelength can penetrate deeper into tissue than can visible light and does not induce DNA damage. Therefore, true in vivo imaging is practical with near-infrared probes. Dyes that absorb energy in the near-infrared region will release heat following exposure to the appropriate wavelength and can kill cancer cells. Therefore, by including such dyes with the chemotherapy agent or incorporating the dye into the drug delivery vehicle, therapy can be targeted since the drug will not be activated until it has reached its intended target. The therapy is image guided because the probe/therapeutic drug can be detected in vivo. Compared to optical imaging, Positron Emission Tomography (PET) has the advantage of greater resolution and greatly reduced attenuation and scattering. In addition, the radiolabeling of drugs or biochemically important molecules with PET isotopes is much simpler, and typically results in chemicals with similar or identical properties to the original chemical. Such imaging approaches have been applied to understand the molecular basis of diseases, biochemical processes, gene delivery and expression, tissue receptor-ligand activity, enzyme mediated processes, drug discovery, monitoring novel therapy techniques, etc.
Particles in a size range of 110-140 nm seem to be ideal drug delivery vehicles because they first avoid liver uptake, which filters smaller particles, but are small enough not to be removed by macrophages. For optimal performance, particles should have a small size distribution, uniform surface properties, must be able to complex various molecules very efficiently, must remain in the circulation long enough to be removed by the target tissue rather than the reticuloendothelial system (macrophages), and must be biocompatible and biodegradable. Small particles with neutral surfaces and prepared with polymers of high molecular weights are slowly cleared by macrophages while large particles with high surface potentials and prepared with polymers of low molecular weights are rapidly cleared by the macrophages. Nanoparticles coated with a higher molecular weight dextran or poly-ethylene-glycol (PEG) leads to a decrease of the surface charge, which increases their circulation time. Nanoparticles (polymer or liposomes) can be modified to target specific cells and designed to carry multiple therapeutic agents and multiple imaging probes.
Radiochemistry and Dosimetry
We are developing PET radiochemicals that report regional metabolic/functional variables of various organs or tumors, and examining their cellular uptake kinetics. In addition to clinical studies, tests are conducted in whole animal, isolated organ and isolated cell models. We are developing tools for automatic segmentation and registration of organs and tumors to accurately determine tumor functional and anatomical volumes which is required for accurate dosimetry calculations for Selective Internal Radiation Therapy (SIRT) planning. http://www.nuclearoncology.org/
PET/CT image of a patient with liver cancer demonstrating the mismatch between the functional and anatomical size of the tumor, which can negatively impact patient response to therapy.
Respiratory Gated Positron Emission Tomography (PET)
PET glucose metabolism is often used to diagnose cancer since the fast growing highly metabolic tumor requires more energy than surrounding tissue. An accurate diagnosis requires a precise measure of the size of the tumor. But, due to the movement of the lungs during respiration, obtaining an accurate image of a lung or liver tumors is difficult. We are developing instrumentation and imaging processing algorithms to gate the PET camera acquisition with the patient’s respiratory motion to reduce the lung motion artifacts. Recently PET has been combined with CT, which provides anatomy. In addition to supplying an anatomic reference for the PET metabolic image, the CT is also used to correct for attenuation of the PET to improve image quality. In order to apply CT attenuation correction to imagines of tissue in the lung, a computer-assisted automatic identification of lung lesions in the PET/CT images is being developed to account for the movement of the lungs during the PET imaging.
Left: PET and CT images from a GE Discover LS Hybrid PET/CT from Baptist Hospital of Miami. From left to right are the CT, PET, and PET/CT fused images. Right: PET image of a dynamic lung phantom imaged with the tumor (a) static, (b) the tumor moving, and (c) after motion correction.
Nanoscale Drug Design and Delivery for Improved Cancer Diagnosis and Therapy
Cancer is the second leading cause of death in the US, exceeded only by heart disease. Early detection of small primary tumors is critical for successful therapy and improved survival rates. Chemotherapy is often the first choice for treating many cancers. It is critical that the chemical be sequestered only in the target tissue at toxic concentrations so that nontarget tissue exposure is minimized. However, it is often difficult to ensure that the chemotherapy targets only the cancer and further that the chemical is localizing in the target tissue. Cancer cells easily take up extremely small (nano-sized) particles. New technologies are being developed to allow for the creation of complex nanoscale materials as drug delivery vehicles and sensors. Combining therapy with imaging has the potential to enhance the efficacy of treatment by ensuring and verifying that the drug reaches the target tissue, while minimizing nontarget tissue uptake. Light in the near-infrared (NIR) wavelength can easily pass through tissue and therefore, NIR fluorescent tracers can be used for imaging. Dyes that absorb energy may also release heat following exposure to the appropriate wavelength light and kill cancer cells. With a light sensitive dye incorporated into the drug delivery vehicle, therapy can be targeted since the drug won’t be activated with a laser until the drug has reached its intended target. The long term objective of this study is to develop a methodology of improved diagnosis and treatment of cancer by combining therapy and imaging in the same drug. The study is a collaboration of engineers, chemists, biologists, and clinicians with expertise in drug design, drug delivery modeling, and experimental models of cancer.
Schematic of multimodal targeted polymer nanoparticle.
Upper Left: Indocyanine Green (ICG) loaded polymer nanoparticles in cancer cells. Upper Right Doxorubicin (DOX) loaded polymer nanoparticles in cancer cells. Lower Left: Free DOX localizes in the nucleus (green) of cancer cells while free ICG localizes in the cytosol (red). Lower Right. Antibody-conjugated DOX loaded polymer naoparticles in cancer cells containing antibody specific membrane receptors.