Pharmaceutical biologics has gained popularity in treating many diseases. Several top 10 sales medicines in 2017 are biologics. The instability of many pharmaceutical biologics in solution may necessitate the development of a product in the solid form, which often shows enhanced stability. For pharmaceutical biological solids, the mainstay manufacturing technique is lyophilization, which is a time-consuming (e.g. 48 hours) batch process with very low energy efficiency. Innovative drying techniques have gained increasing interests for manufacturing biopharmaceutical solids because it can be developed into a continuous process with high throughput, and has the capability to achieve satisfactory powder flow by manipulating particle properties.

Dr. Zhou’s research has explored innovative drying techniques to manufacture biological solids for improving manufacturing and delivery performance. He has developed protein solid formulations using spray drying and understood the impact of surface properties on physical stability using the advanced protein solid-state technique of solid-state hydrogen/deuterium exchange with mass spectrometry (ssHDX-MS, through collaboration with Dr. Elizabeth Topp) and solid-state NMR (with Dr. Eric Munson) and the surface characterization platform.

Future work includes utilization of other innovative techniques such as spray freeze drying and electrospray drying for production of heat-sensitive biological products. The success of this work could revolutionize the manufacturing of pharmaceutical biological solid products. This work has attracted several grants from National Institute for Innovation in Manufacturing Biopharmaceuticals and many pharmaceutical industry grants with Genentech, AstraZeneca and Merck.

Besides formulation design, understanding pulmonary drug delivery process is critical to ensure treatment efficacy of inhalation medicines. Deposition and disposition of inhaled formulations after pulmonary delivery is pivotal to optimize their in vivo efficacy and to minimize toxicity. In contrast to oral and parenteral administrations that have been extensively examined, research in pulmonary drug delivery systems is still in its infancy. There is little information in the literature on how the drugs are absorbed, distributed, and eliminated from the lungs, particularly for novel formulations such as liposomes. Given the fact that the first inhaled liposomal product was approved by FDA in 2018 (Arikayce®, amikacin liposome inhalation suspension), there is an urgent need to understand the pulmonary drug delivery process so as to optimize efficacy and minimize toxicity. 

 Dr. Zhou’s research in pulmonary drug delivery focuses on understanding the drug disposition behavior of inhaled formulations using both cell and animal models. Human lung epithelial cell models using A549 and Calu-3 cell lines have been established and employed to understand toxicity and drug transport of inhaled formulations in Dr. Zhou’s lab. Through the collaborations with Dr. Fanfan Zhou at the University of Sydney and Dr. Jian Li at Monash University, the major transporters involved in disposition of antibiotics have been identified and the mechanisms of lung toxicity by polymyxins (polypeptide antibiotics) have been demonstrated. Together with his collaborators at Monash University, Dr. Zhou has established an animal pharmacokinetics/pharmacodynamics/toxicodynamics model to evaluate in vivo efficacy and to optimize dosage regimens of inhaled therapies. 

Future studies include advanced imaging to elucidate drug disposition of inhaled drugs in a 3D human lung epithelial tissue model. The current A549 and Calu-3 are human cancer cells, which are cultured as a monolayer. Dr. Zhou has developed a 3D human lung epithelial tissue model for evaluating inhaled formulations, which contains essential components of lung epithelium including ciliated apical surface, mucociliary epithelium, stromal fibroblasts and pulmonary macrophage. Drug transport and absorption in each of these components can be determined through fluoresce- or 3H-labeling of drugs followed by cell separation and imaging. Through collaborations with Dr. Jian Li of Monash University, cutting-edge imaging techniques such as matrix-assisted laser desorption ionization - Fourier transform mass spectrometry (MALDI-FTMS) and synchrotron X-ray fluorescence microscopy (XFM) will be developed to understand drug disposition and toxicity of inhaled medicines in both proposed in vitro 3D lung tissue models and established in vivo animal models.