Hanh Thuy Nguyen

Poor stability of biological products such as proteins is a major challenge facing the biopharmaceutical industry. Poor stability is usually mitigated by formulating these products in the solid state, employing sugars as stabilizers. Several studies have pointed out the superior stabilizing ability of disaccharides, including sucrose and trehalose, as compared to polysaccharides such as dextrans. The aim of this study was to investigate the impact of excipient molecular weight on miscibility with a model protein, bovine serum albumin (BSA). Aqueous solutions containing a binary combination of a sugar-based stabilizer and BSA were dried using different methods (air drying to form films, spray drying, and lyophilization). The stabilizers tested varied in molecular weight and were dextran 6, 70, or 2000 kDa, hydroxypropyl methyl cellulose (HPMC), and trehalose. Miscibility was evaluated using a variety of techniques including confocal fluorescence microcopy, infrared and Raman microscopy, and solid-state nuclear magnetic resonance (ssNMR) spectroscopy. The stability of BSA in dried mixtures subjected to accelerated storage conditions was also measured. BSA was more stable in the presence of dextran 2000 kDa compared to dextran 70 and 6 kDa, while stability was highest in trehalose and lowest in HPMC. From ssNMR spectroscopy, BSA-Dex 2000 kDa and BSA-trehalose were miscible over 20 and 5 nm length scales, BSA-Dex 6 kDa was miscible over a 20 nm length scale and phase-separated over a 5 nm length scale, while BSA-Dex 70 kDa and BSA-HPMC were phase-separated over both length scales. It was postulated that for dextran, the size of the polysaccharide relative to the size of the protein determined the extent of the system miscibility and stability. A smaller or similar polysaccharide size compared to that of the protein, as in the case of BSA-Dex 6 kDa and BSA-Dex 70 kDa, leads to depletion-induced phase separation. A much larger polysaccharide size compared to that of the protein allows the protein molecules to be trapped within a polysaccharide mesh, resulting in a miscible system. This study suggests that the impact of the relative size of the stabilizer and protein on miscibility is more complex than previously considered.

Inorganic nanomaterial (INM)-based combination cancer therapies have been extensively employed over the past two decades because of their benefits over traditional chemo- and radio-therapies. However, issues regarding the toxicity and accumulation of INMs in the body have arisen. This problem may be improved through the use of biodegradable or disintegratable nanosystems such as black phosphorus (BP). Challenges to the manufacture of fully nanodimensional BP remain. In addition, improvements in recently developed cancer immunotherapies require their incorporation with drugs, targeting agents, and delivery vehicles. With these needs in mind, this study develops a method for instant in-flight manufacture of nanodimensional BP using plug-and-play devices for subsequent assembly of photoimmunotherapeutic [email protected] composites containing mutated B-raf inhibitors (dabrafenib), immune checkpoint inhibitors (PD-L1), and cancer-targeting antibodies (CXCR4). The resulting nanocomposites exhibited cancer targetability and regulatability of PD-L1 expression both in vitro and in vivo. These activities were further increased upon near-infrared irradiation due to the incorporation of a phototherapeutic component. These results suggest that these nanocomposites are promising as a new class of advanced cancer therapeutic agents.