Harvard Catalyst Profiles

Our mission is to create a novel medical imaging methodology using near-infrared light and advance our understanding of immunology and immunotherapy. Our central focus has been to develop a new imaging technology to dissect the immune response in the context of cancer, allergy, and infectious diseases with the ultimate goal of translating the knowledge into clinical practice. For example, our group successfully established (1) near-infrared imaging technology of immune components including vaccines and exosomes to improve immunotherapy and (2) molecular imaging of cancer signaling to develop a novel targeted cancer therapy. We are also working to establish safe, effective, simple, and affordable immunotherapy for infectious diseases, allergies, autoimmune diseases, and cancer using near-infrared laser technology. 1. Immunotherapy imaging Once a vaccine or immunotherapeutic is injected, it has to reach the right location called “secondary lymphoid tissue” to be effective. However, there is no non-invasive method to describe its behavior in a real-time manner. We are solving this issue to create a reliable monitoring strategy for vaccine or immunotherapeutic imaging using renal clearable zwitterionic near-infrared fluorophores with high target-to-background ratios. Recently, we demonstrated the size-dependent transportation of vaccine from the injection site to the secondary lymphoid tissues using a multispectral near-infrared imaging platform. In this program, we aim to develop a novel technology that can be used to optimize formulation and evaluate the safety of vaccines and immunotherapeutics. 2. Immuno-oncology imaging Pre- and post-operative and intraoperative cancer imaging is critical for the management of cancer patients. However, traditional imaging including CT, MRI, and ultrasound is not good enough to precisely describe the location of small cancers. We are solving this issue by creating a high-sensitive and specific imaging modality. Recently, we established a reliable imaging method with a high signal-to-background ratio using TLR4 antibody conjugated with a renal clearable zwitterionic near-infrared fluorophore. In this project, we were able to image liver cancer in real-time after a single intravenous injection of TLR4-targeted near-infrared fluorophores over 3 days under the NIR fluorescence imaging system. The probe was determined to target tumor-associated macrophages resulting in specific imaging of liver cancer which is enriched with tumor-associated macrophages. This method can be further extended for intraoperative imaging of many types of cancer. 3. Laser adjuvant technology To boost the immune system, we have been traditionally using chemicals and biologicals. However, they may induce adverse effects. We are working to create a novel solution using “laser light”. Recently, we have shown that skin treatment with near-infrared laser light boosts the immune response to vaccines. This “laser adjuvant” has numerous advantages over the historical chemical or biological agents; it is free from cold-chain storage, hypodermic needles, biohazardous sharp waste, irreversible formulation with vaccine antigen, undesirable biodistribution in vital organs or unknown long-term toxicity. In addition, laser technology has been used in the clinic for more than three decades and is therefore technically matured and safe. Since vaccine formulations are given to healthy populations, these characteristics render the “laser adjuvant” significant advantages for clinical use and open a new developmental path for a safe and effective vaccine. 4. Immune-function imaging Real-time assessment of immune cell function is challenging. In order to resolve this issue, we recently developed a new optical platform equipped with two distinct wavelengths of lasers to realize high-throughput single cell live immune cell imaging. Using this technology, we successfully observed mitochondrial retrograde signaling including intracellular calcium and reactive oxygen species (ROS) in a large number of T cells simultaneously. This technology could be further used to study the function of other types of immune cells.

The Bioengineering & Nanomedicine (BENMD) Program has been trying to solve an important clinical problem, “curing cancer”, by applying the first principles of chemistry and engineering. To achieve this goal, we have a multi-disciplinary team of researchers including chemists, engineers, biologists, physicists, and surgeons. This is a very unique environment, where experts from several fields come together and work together to achieve the same goal. The BENMD program is conceptually organized into four areas: 1) targeted chemistry agents development, 2) engineering bioengineered devices, 3) image-guided drug delivery, and 4) immuno-oncology imaging. Although much of our research is multi-modality, including MRI, SPECT, and PET, our primary focus is near-infrared (NIR) fluorescence imaging and its clinical application. NIR light is invisible to the human eye, but is capable of penetrating relatively deeply into living tissue. The field was so new when we started that few imaging systems or contrast agents even existed. Our Imaging Center took a lead in imaging system development, and invented an intraoperative NIR fluorescence imaging system that permits anatomy and function to be visualized simultaneously, in real-time, with high sensitivity, and with no moving parts. This system provides complete image guidance to surgeons during tumor resection, sentinel lymph node mapping, and other surgery in which a tissue target must be detected, assessed, or resected. We have described versions of this imaging system that are optimized for small animal or large animal/human use. Contrast for our imaging system is provided by exogenously introduced NIR fluorophores. Here, too, our BENMD program has taken a lead role in the field. To date we have developed robust methods for synthesizing organic contrast agents based on tetra-sulfonated heptamethine indocyanines, as well as inorganic/organic contrast agents based on quantum dots and organic fluorophores. In each case, we have published detailed methods that have advanced the field. Moreover, to date, our BENMD program has developed specific NIR fluorescent contrast agents for NIR fluorescence angiography, sentinel lymph node mapping, vascular mapping, quantitative assessment of tissue perfusion, and detection of hydroxyapatite calcification. In addition, manuscripts in preparation or review include those describing NIR fluorescent contrast agents for high-sensitivity detection of cellular injury and death, targeted cancer therapy, inflammatory diseases, and real-time image-guided drug delivery to the brain, bone, cartilage, nerve, brown fat, lymphoid tissues, and endocrine glands. Currently, the BENMD Program consists of over 20 staff members of scientists, postdoctoral fellows, graduate students, and technicians. We are combining our advanced chemistry and engineering experience with an advanced understanding of animal/human physiology to develop a new class of contrast agents for image-guided interventions in oncology. Through the rich infrastructure and scientific environment at MGH Radiology, we will try to combine our optical imaging technology with nuclear medicine, which could provide anatomic and functional imaging and treatment of human cancers. To that extent, the BENMD program provides an Optical Core and a Mass Core to the MGH and Harvard research communities for elucidating the mechanism of action of small molecules by converting them to NIR-PET, NIR-SPECT, NIR-CT, and NIR-MR multimodal imaging agents. By developing targeted imaging probes that are able to localize in the cancerous tissue, we will be able to provide healthcare professionals with a new method to both detect and treat these tumors, through radioimaging and/or laparoscopic imaging as well as image-guided surgery.