438258 Seeing Is Believing - Macrophage-Targeted Theranosis

Sunday, November 8, 2015
Exhibit Hall 1 (Salt Palace Convention Center)
Rahul Keswani, University of Michigan, Ann Arbor, MI

While advanced genetic technologies, precise drug synthesis chemistry and controlled release systems have resulted in remarkable progress in the field of personalized medicine, gene and cell therapy; critical barriers – untargeted therapy, immune system defense & active non-invasive therapy monitoring – continue to hamper the realization of superlative medical treatments. Perhaps, the optimal way to design therapeutics would be to seek out our natural defense mechanisms and empower them with the potential to either transport the therapeutic or treat the disorder themselves while allowing the active monitoring of the therapy. My research interests lie in the development of such intelligent therapeutics via self-assembly and depot formulations of drug or gene theranostics (therapy + diagnostics).

The immune system is remarkably efficient in defending the human body from unwanted pathogens. Unfortunately, the same defense mechanisms disallow most current therapeutics from performing to their full potential due to ill-serving pharmacology leading to inefficient biodistribution and targeting. Pharmaceutical research has advanced to the point wherein the application of current advanced bioinspired materials such as synthetic lipids, biopolymers, polymersomes, cell-derived supramolecular structures such as exosomes combined with functional moieties such as active pharmaceutical ingredients, genetic constructs, hormones and peptides can be used to generate super-therapeutics and advanced synthetic viruses that can deliver the desired therapy. My research focus is to use the aforementioned toolkit and add immune cell targeting via specific linkers and targeting moieties and theranostic elements – such as dye molecules, contrast agents, activated peptides, acoustic probes amongst others. This would enable the design of a library of smart theranostics with a range of pharmacological activity and detection capabilities.

My first plan of action would be to target macrophages– capable systemic immune cells that can transport and distribute foreign supramolecular assemblies. Macrophages are immune cells with unparalleled capabilities to reach diseased locations such as tumors, tissue inflammation, infections and physical injury. Targeting macrophages could have a dual purpose – one, to either transport the therapy to their intended site of action or two, provide the necessary therapy themselves via promotion of their natural defense mechanisms. For example, such a strategy could be used to target synovial macrophages for arthritic theranostic therapy or peritoneal macrophages for theranostic therapy of systemic inflammation and bacterial infections.

Additional design elements would come from ligands or peptides that would modulate the pharmacology of intracellular interactions or binding to the intended site. This library of theranostic treatments could be further expanded to include new epigenetic and gene editing/regulating based therapies such as DNA methyltransferase (DNMT) inhibitors and CRISPR-associated genetic switches as well as the inclusion of more complex contrast agents which can be detected via PET, CT scans and microwave medical imaging. Overall, these design principles represent a strong leap forward in the field of pharmaceutics design and theranosis that can lead to significant advancement in global medicinal practice and personalized medicine.

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