Research topics

Introduction

Our research leverages the power of chemical synthesis to develop new tools for studying and modulating the innate immune system. This includes synthesizing novel drugs, nanotherapeutics, and imaging tracers, but also studying their behavior and effects in vivo. Our work has a strong emphasis on organ transplantation, cancer, and cardiovascular disease, for which we closely collaborate with immunologists and imaging scientists. Although our work predominantly focuses on mouse models, we also initiate the clinical translation of our technologies by experiments in rabbits, pigs, and non-human primates.

Therapeutically Targeting Trained Immunity

Immunological memory has long been regarded as an exclusive hallmark of the adaptive immune system. However, this dogma has been challenged by a growing body of literature, demonstrating a de facto immune memory within the innate immune system. This innate immune memory, termed ‘trained immunity’ is regulated by epigenetic changes in innate immune cells and their progenitors in the bone marrow. These modifications endow innate immune cells with the ability to ‘remember’ previous stimuli (e.g., an encounter with a pathogen or DAMP) and hyperrespond to subsequent stimuli, both related and unrelated. Judiciously regulating trained immunity in vivo holds great potential in treating conditions characterized by a dysregulated immune system, including cancer, infectious diseases, and organ transplant rejection. However, this strategy requires delivering trained immunity-regulating drugs to myeloid (progenitor) cells in the bone marrow. To achieve this, we have developed lipoprotein-based nanocarriers, termed ‘nanobiologics’. Nanobiologics have a high myeloid cell-avidity and can be loaded with diverse small molecule drugs using a prodrug strategy developed by us. We have extensively used nanobiologics to study and treat disease in mouse models. Furthermore, we have demonstrated these nanotherapeutics’ clinical potential by using them to significantly prolong graft survival in non-human primate models of heart and lung transplantation.

Developing Immuno-PET Probes

Biomedical imaging facilitates non-invasively studying (bio)materials’ in vivo.  The high sensitivity and quantitative nature of PET imaging make it an especially effective aproach. We routinely radiolabel biomolecules and nanotherapeutics to evaluate their pharmacokinetics and biodistribution. We also study the immunological effects of conditions or therapies using innovative immuno-PET probes. For instance, we developed nanobody-based imaging protocols for longitudinally tracking the distribution and dynamics of distinct immune cell subsets in vivo in murine transplant models. Lastly, to gain molecular-level insights, we leverage synthetic chemistry to develop small molecule radiotracers for monitoring metabolic and epigenetic processes. Our imaging studies are performed using the state-of-the-art facilities of Mount Sinai’s BioMedical Engineering and Imaging Institute (PET/CT and PET/MRI) and in both small and large animal models. 

Photodynamic therapy

Photodynamic therapy uses light and a photosensitzer to produce reactive oxygen species (ROS) in vivo and therapy locally damage cancerous tissue. Besides directly damaging tumor cells, photodynamic therapy also produces inflammation which can reduce help tumor growth and potentiate other therapies. As most photosensitizers (e.g., porphyrins) display poor tumor accumulation and retention, they are typically formulated into nanocarriers. We are evaluating the effects of combining photodynamic therapy with clinically-relevant immunotherapies and assessing their effects on trained immunity and the tumor microenvironment.