Dr. Songping Huang: Nanomedicine – Development of Novel Nanoparticles to Target the Vulnerability of Iron Metabolism for Treating Bacterial Infections

Thus far antibiotics have underpinned modern medicine for well over 70 years. Their use has reduced childhood mortality, increased life expectancy, made invasive surgery and organ transplant possible, and ensured the safety of cancer chemotherapy, to name just a few. Meanwhile, in response to the widespread use and misuse of antibiotics in humans and animals, bacterial pathogens have accelerated the process of mutation to develop drug resistance to these medicines.  As a result, drug-resistant bacterial pathogens have started to spread faster than the discovery of new antibiotics. It is estimated that more than 30% of clinical isolates of Pseudomonas aeruginosa (P. aeruginosa) from the patients in any given intensive care unit (ICU) or a nursing home are now resistant to three or more antibiotic drugs. The situation is very similar for other pathogenic organisms. It is alarming to note that some strains have become resistant to virtually all the commonly available antimicrobial agents.

Iron is an essential element for nearly all forms of life. In the battle between the invading pathogenic microorganisms and the host vertebrates for this strategic micronutrient, evolution seems to have granted vertebrates the upper hand over pathogenic bacteria. For example, nature has developed sophisticated machinery in vertebrates to sequester, transport and store iron with an extremely high efficiency to tightly regulate the amount of free iron at both the systemic and cellular level, which significantly decreases the chance for the invading pathogenic bacteria to multiply and cause disease. In contrast, pathogenic microorganisms totally depend on the iron pool of the host vertebrate for iron supply and acquire iron by means of theft and robbery. At the time of infection, one of the host defense mechanisms is to withhold iron from invading pathogens. This iron withholding process, often referred to as nutritional immunity, mobilizes a score of iron transport and storage proteins to restrict the availability of free iron.

We are developing two types of novel nano-particles for such applications: the first type of nano-particle has the ability to deplete intracellular iron in pathogenic bacteria, and the second type of nano-particle can act as a “Trojan horse” to deliver gallium - the so-called fake ion in biology, to interfere with iron metabolism in the pathogenic bacteria in which the stress of iron starvation has been produced by the first type. The tandem application of the first type followed by the second type of nano-particles will then produce a potential synergistic effect to deliver a deadly blow to the drug-resistant bacteria. This unconventional strategy for combating the MDROs will evade all the known mechanisms of bacterial resistance to antibiotics that include: (1) the enzymatic degradation of antibacterial drug molecules, (2) an alteration of bacterial proteins targeted by antibacterial drugs to reduce their binding capacity, and (3) a change in membrane permeability to antibacterial drugs. Therefore, we believe that our approach of using the nano-particles for these purposes is not only capable of producing high efficacy in treating bacterial infections, but also has potential to evade or circumvent all of the above-mentioned mechanisms for drug resistance.

Selected Publications:

1. Perera VS, Chen G, Cai Q and Huang SD. Nanoparticles of gadolinium-incorporated Prussian blue with PEG coating as an effective oral MRI contrast agent for gastrointestinal tract imaging. Analyst. 141(6): 2016-2022, 2016. DOI: 10.1039/C5AN01873K
2. Kandanapitiye MS, Gott MD, Sharits A, Jurisson SS, Woodward PM, Huang SD. Incorporation of gallium-68 into the crystal structure of Prussian blue to form K⁶⁸GaxFe_1-x[Fe(CN)₆] nanoparticles: toward a novel bimodal PET/MRI imaging agent. Dalton Trans.; 45(22): 9174-9181, 2016. DOI: 10.1039/C6DT00962J
3. Huang SD. Chapter 20: Bismuth-based nanoparticles for CT imaging. In Design and applications of nanoparticles in biomedical imaging, Bulte JWM and Modo MMJ (eds.), Springer International Publishing in Switzerland November 26, 2016, p429-p444.  Available at Springer Link
4. Ye, HY, Liao, WQ, Zhou, Q, Zhang, Y. Wang, J, You, YM, Wang, JY, Chen, ZN, Li, PF, Fu, DW, Huang SD, Xioang, RG. Dielectric and ferroelectric sensing based on molecular recognition in Cu(1,10-phenlothroline)₂SeO₄ systems. Nature Communications, 8: 14551, 2017.  DOI:10.1038/ncomms14551 10, 132, 16873–16882.