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This drug platform employs living multicellular assemblies that can deliver drug molecules in controlled patterns to specific tissues in order to perform complex therapeutic functions. Unlike standard small-molecule drugs and biopharmaceuticals, living drugs are therapeutic systems composed of living cells, which are able to perform medical functions. Most living drugs use genetically engineered cells of a single type, as with CAR T cell therapy, which has been successful in treating certain cancers, and stem cell-based therapies, which have treated other diseases effectively. However, relying on just one cell limits the potential functionality of living drugs.
Researchers at the University of Florida have developed a system to create multicellular living drugs made up of two or more types of alive cells (i.e., drug-secreting and supporting cells) that can work together to perform complex therapeutic functions. The choice of alive cells includes genetically programmed prokaryotic cells, eukaryotic cells, or a mixture of both. This new class of medicine employs a capsule that hydrolyzes in specific tissue areas to release the multiple types of cells selectively, controlling dose and duration. The multiple types of cells can perform various functions, including secreting specific drug molecules in programmed combinations or sensing a disease via associated biomarkers.
New class of multicellular living drugs that increase retention, viability, and drug-secreting efficacy in targeted host tissues
Multicellular living drugs are isolated micro-ecosystems comprised of nano-bio-engineered assemblies of living cells, which include three major components to act as medicines. A cross-linked polymer boundary shell provides protection for the cells and controls the uptake of nutrient molecules. Functional cells within the shell are programmed to perform a variety of tasks such as synthesizing molecular drugs, assisting in metabolism, and transporting substances into the extracellular space. The third component is a collection of supporting cells, programmed genetic circuits that maintain homeostasis in the living drugs, regulate the release of products from functional cells, and eliminate the living drugs once their therapeutic purpose is over.
These new nuclear-protein-delivery materials provide more efficient cellular reprogramming that, by eliminating need for genetic modification, is more acceptable to regulatory agencies. These reprogrammed cells can be used in regenerative therapy for genetic, metabolic and degenerative disorders. It has been known for several years that it’s possible to reprogram the nucleus of both differentiated and undifferentiated cells by expressing exogenous transcription factors. However, introduction of additional genetic material into the cells being reprogrammed can lead to genetic instability and formation of cancerous cells. To circumvent issues associated with the use of DNA or RNA to reprogram cells, researchers at the University of Florida have taken advantage of a bacterial system to introduce nuclear proteins directly into the host cells. These specific bacteria have been engineered to eliminate toxicity toward the host cell while maintaining the ability to efficiently inject proteins, such as transcription factors, into mammalian cells. Following protein delivery and cell reprogramming, antibiotics are used for easy and efficient elimination of bacteria from host cells. This technology promises to be much more efficient than alternative methods and also more acceptable to regulatory agencies because there are no genetic modifications of the reprogrammed cells.
Regenerative therapy for genetic, metabolic and degenerative disorders
A modified Pseudomonas aeruginosa type III secretion system (T3SS) has been developed that efficiently delivers selected proteins into a host cell. Several gram-negative bacteria, such as Pseudomonas aeruginosa, possess a structure identified as the T3SS, a naturally occurring protein-delivery mechanism. Bacterial proteins are injected directly into the cytoplasmic compartments of the host cells. This technology offers a highly effective system for delivering proteins into eukaryotic cells, introducing reprogramming factors directly into a host cell through a needle-like structure on the bacterial surface.
This series of antibacterial agents, known as the halogenated phenazines, are able to eradicate free-floating (planktonic) bacteria in addition to persistent, surface-attached bacterial biofilms against gram positive organisms such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE) and vancomycin-resistant Enterococcus faecium (VRE). Bacterial cells housed within a biofilm are metabolically dormant, persister cells that display high levels of tolerance towards conventional antibiotics and biocides. Bacterial biofilms occur in the majority of bacterial infections and accumulate on essentially all surface types, including medical implants and industrial pipes. Researchers at the University of Florida have discovered halogenated phenazine small molecules that are able to eradicate greater than 99.9 percent of biofilm cells through a mechanism that is non-toxic to mammalian cell lines, including red blood cells. In addition, select halogenated phenazine analogues have potent antibacterial activities against the slow-growing human pathogen Mycobacterium tuberculosis.
Clinical and non-clinical applications for eradicating biofilm-associated bacterial pathogens and surfaces colonized by persistent biofilms.
The halogenated phenazine scaffold is highly tunable, which has been demonstrated through the synthesis and evaluation of more than 80 synthetic analogues. Continued efforts are underway to further develop halogenated phenazines for numerous applications related to bacterial biofilm infections and disinfectants. These halogenated phenazines have demonstrated the most potent biofilm eradication activities reported in the literature against MRSA, MRSE and VRE biofilms. In addition to biofilms, select halogenated phenazine analogues demonstrate potent antibacterial activity against M. tuberculosis.
