Research in the Zhang lab addresses numerous challenges to drug and vaccine delivery using nanoparticles, including immune evasion and reversible liposome stabilization. Their most clinically relevant work relates to the prevention and treatment of infectious disease and cancer.
The Zhang group is best known for their introduction of polymeric nanoparticles coated with red blood cell (RBC) membranes to evade immune clearance, the major challenge to systemic drug delivery using nanoparticles. While a simple synthetic coating (polyethylene glycol (PEG)) is widely used for this purpose, blood type-matched or autologous RBC membranes are less likely to trigger an immune response, which has been observed against PEG. Even more creative are the lab’s later uses of these particles: to remove bacterial toxins from the bloodstream and to deliver vaccine antigens. The latter application overcomes a major limitation of heat-denatured toxoid vaccines; denaturation often alters toxin structure, limiting vaccine potency.
Another major challenge in the field of nanomedicine is the instability of liposomes, which have numerous advantages for drug delivery, including the ability to fuse with the plasma membrane to deliver molecules into the cytosol. However, these structures are prone to fusion with one another, which shortens their shelf life and lowers their delivery efficiency. While PEG is often used to stabilize liposomes, this coating can prevent fusion with cells and resulting drug release. Thus, another major avenue of investigation in the Zhang lab is the development of strategies to stabilize liposomes in such a way that the disease environment triggers fusion with cells. One solution is to incorporate a responsive moiety into the link between PEG and its membrane anchor; Zhang’s team has created a pH-responsive system of this type that could be useful for delivery to tumors, which have a slightly lower than normal extracellular pH. The team has also developed a chitosan-modified gold nanoparticle-stabilization strategy; such liposomes are disrupted by bacterial toxins, or, if the liposomes incorporate negatively charged lipids for stability at very low pH (such as that of stomach acid), by neutral pH.
The Zhang lab’s interest in nanomedicine for infectious disease has also led them to develop potential therapeutics based on a fundamental advantage of liposomes: their ability to deliver hydrophobic drugs. Several free fatty acids have recently been shown to have strong antibacterial activity, but their clinical translation requires stable, water-soluble formulations. In vivo studies with these natural products have led to multiple drug candidates: liposomal lauric acid for chronic acne, and liposomal oleic acid for drug-resistant Staphylococcus aureus.
CMJ Hu, L Zhang, S Aryal, C Cheung, RH Fang, L Zhang. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. Proc Nat Acad Sci USA 2011; 108(27), 10980-85.
D Pornpattananangkul, L Zhang, S Olson, S Aryal, M Obonyo, K Vecchio, CM Huang, LZhang. Bacterial toxin-triggered drug release from gold nanoparticle-stabilized liposomes for the treatment of bacterial infection, J Am Chem Soc 2011; 133 (11), 4132-39.