Nature is a magician, full of complexity and creativity. Compounds derived from natural products have been one of the most important sources for drug discovery and development1. Also, nature provides important guidance for drug delivery and tissue engineering2. My lab is focusing on development of biomaterials and their therapeutic applications. When we design new biomaterials and therapeutics, we learn from nature.
We always see multiple vitamins in pharmacy stores. Vitamins are natural components for a wide variety of cell pathways and functions. Chemically, they possess unique and diverse functional moieties such as hydrophobic chains, hydroxyl groups, and positive charges, which may be incorporated into our nanoparticle components. In 2015, I discussed the idea with Dr. Xinfu Zhang, a postdoctoral scholar in my lab. Dr. Zhang, specialized in chemical synthesis, quickly drew synthetic routes to different vitamin derivatives such as vitamin A, B, C, D, E etc. Although the reactions look straightforward, vitamins have distinct chemical structures and reactivity. Dr. Zhang spent plenty of time on solving the chemical challenges and finally achieved the synthesis of a set of vitamin derivatives. Then, we formulated these vitamin derivatives into vitamin lipid nanoparticles and examined their delivery in a series of cell types. Mr. Xucheng Hou, a graduate student, found vitamin c lipid nanoparticles (VcLNPs) is an efficient delivery vehicle for macrophages. Meanwhile, Xucheng was interested in applying macrophages to sepsis therapy. He went through a large amount of literature. Learning from nature such as the post-translational process of mRNA and the immune escape mechanisms of bacteria3,4, he designed an antimicrobial payload for macrophage. That is an mRNA encoding antimicrobial peptides linked to cathepsin B5.
Figure 1. Inspiration from nature: an orange to a nanoparticle, and then to a cell therapy. VcLNP: Vitamin C lipid nanoparticles; MAC: Macrophage containing antimicrobial peptides linked to cathepsin B in the lysosomes.
With these essential components (Figure 1), we hypothesized that adoptive transfer of macrophages containing antimicrobial peptides linked to cathepsin B in the lysosomes (MACs) may enable the immunocompromised sepsis host to boost innate immunity, prevent bacterial immune evasion, and eliminate multi-drug resistant (MDR) bacteria. Then followed a long time of experimental tests in cell and animal models. During the process of troubleshooting, there were lots of frustrations and excitements. Eventually, we constructed MACs from primary mouse monocytes and demonstrated the therapeutic benefits in mouse sepsis models. Now, we are working together with clinicians on the realization of this MACs technology in the clinic. Although there are likely to be further formidable challenges, we hope this treatment strategy can provide a more effective therapy for sepsis patients in the near future.
Our paper: Hou, X., Zhang, X., Zhao, W., Zeng, C., Deng, B., McComb, D. W., Du, Shi., Zhang, C., Li, W., Dong, Y*., Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis, Nature Nanotechnology, 2020. doi:10.1038/s41565-019-0600-1. https://www.nature.com/articles/s41565-019-0600-1
1. Lee, K.-H. Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach. Journal of natural products 73, 500-516 (2010).
2. Langer, R. & Vacanti, J.P. Tissue engineering. Science 260, 920-926 (1993).
3. Foster, T.J. Immune evasion by staphylococci. Nature reviews. Microbiology 3, 948-958 (2005).
4. Garzoni, C. & Kelley, W.L. Staphylococcus aureus: new evidence for intracellular persistence. Trends in microbiology 17, 59-65 (2009).
5. Hanewinkel, H., Glössl, J. & Kresse, H. Biosynthesis of cathepsin B in cultured normal and I-cell fibroblasts. Journal of Biological Chemistry 262, 12351-12355 (1987).