Dr. Courtney Fletcher
Development of “Biologic-like” Macromolecular Prodrugs
Dr. Dong Wang
Macromolecular prodrug nanomedicines were previously found to passively target the inflammation and provide potent and sustained resolution of nephritis and arthritis in animal models. While the prodrugs can all effectively ameliorate the inflammatory pathology, they showed distinctively different safety profiles. To explore the potential cause of these differences, we compared their pharmacokinetic and biodistribution (PK/BD) profiles. Overall, the prodrugs with higher molecular weight (MW) were found with much higher systemic and tissue exposure than the one with lower MW, which may explain the different safety profiles. Surprisingly, the presence of the macromolecular prodrugs at the inflammatory pathologies was all short-lived and maintained for only 1-3 days regardless of their MW, which cannot explain the sustained amelioration of nephritis and arthritis (> 1 month), suggesting potentially novel pharmacological mechanisms other than the prolonged local release of parent drug from the prodrug nanomedicine. Preliminary data suggest that the macromolecular prodrugs have a mechanism of action distinctively different from their low MW parent drugs’. The transient exposure of the pathologies to macromolecular prodrugs seems to have led to phenotypic modification of cells associated with inflammation, with sustained biological outcome. As the field of nanomedicine shifting its focus to included autoimmune and inflammatory diseases, this unique pattern of interaction between inflammatory pathology and macromolecular prodrug warrants further investigation.
“Ligand-targeted Imaging and Therapeutic Agents for Cancer, Autoimmune and Infectious Diseases
Dr. Philip Low
We have developed small molecule ligands for use in targeting attached drugs specifically to pathologic cells, thereby avoiding the collateral toxicity that usually occurs in healthy cells. In the case of cancer, we began by exploiting up-regulation of a folate receptor on cancers of the ovary, lung, kidney, endometrium and breast to target imaging and therapeutic agents to these cancers. After experiencing success in this area, we then continued by developing additional targeting ligands for delivery of drugs to cancers that do not over-express a folate receptor. Clinical trials of eight of these ligand-targeted drugs demonstrate that the strategy of drug targeting holds considerable promise for increasing drug potency while reducing unwanted toxicity. Data from these clinical trials and the preclinical discovery and development work that preceded them will be presented in this seminar. Videos on the use of these same tumor-targeting ligands to deliver brightly fluorescent near infrared dyes to “light up” cancer tissues during surgeries will also be presented. Finally, because similar ligand-targeted imaging and therapeutic agents have more recently been developed for a number of autoimmune/inflammatory diseases (e.g. rheumatoid arthritis, idiopathic pulmonary fibrosis, multiple sclerosis, psoriasis, atherosclerosis, osteoarthritis), infectious diseases (e.g. malaria, influenza virus infections, etc.), as well as genetic disorders (e.g. sickle cell disease) and bone fractures, exciting new preclinical and clinical data on these applications will also be described.
Dr. Tejal Desai
Emerging strategies for cancer immunotherapy
Dr. James Moon
With profound advances in immune-oncology, cancer immunotherapy is now considered the fourth pillar of cancer therapy, joining the ranks of surgery, radiotherapy, and chemotherapy. For some cancers, including advanced non-small cell lung cancer, combination immunotherapy is FDA-approved as the frontline therapy, showing promise for applying immunotherapy to a wide range of advanced cancers. However, their dose-limiting toxicities and low patient response rates remain as the major challenges to address. Here, we highlight new opportunities for combination immunotherapy based on nanomedicines that are well poised tackle the challenges faced by the field of cancer immunotherapy. We present biomaterial-based strategies for amplifying anti-tumor immune responses and sensitizing tumors to immunotherapies in a safe and effective manner. Briefly, we show that lipid-based nanodiscs can efficiently co-deliver antigen and immunostimulatory molecules to draining lymph nodes and elicit potent CD8+ cytotoxic T lymphocyte responses directed against tumor antigens, leading to substantially enhanced anti-tumor efficacy in multiple murine tumor models, including colon carcinoma, melanoma, and HPV-induced tumors. In a second research thrust, we have shown that this nano-platform can deliver chemotherapeutic agents in a synergistic manner with immune checkpoint blockers. Owning to the facile production process, robust therapeutic efficacy, and good safety profiles, our nanotechnology offers a powerful and convenient platform for improving cancer immunotherapy.