Poly(lactide-co-glycolide) (PLGA) has been widely applied in microspheres (MS) as a protein delivery carrier. However, proteins undergo physical and chemical denaturation during the fabrication of PLGA MS and release in the body. In addition, such formulations often cause undesirable and unpredictable release profiles, characterized by a burst effect and incomplete release. This makes PLGA MS appraoch unsuccessful for most labile proteins. The results from our preliminary study are a clear pointer to the validity of the role played by PEG-polycation (poly(L-histidine)) as a pH-dependent 'reversible molecular shield' in 1) preserving protein structure and preventing aggregation at water/organic interface, 2) exerting a pH buffering (protein sponge effect) in PLGA MS, 3) enhancing protein's physical stability in solution and in MS, and 4) an overall better control over release of the proteins from the PLGA MS ('all-in-one' concept). Although our preliminary results demonstrate the feasibility, there are still a number of variables which can be altered to optimize or tailor this polymer design for specific proteins, such as insulin. This includes changing the size of polyHis and copolymerizing with other amino acids to alter charge spacing or polyHis conformation. The proposal goes well beyond therapeutic proteins in suggesting potential applications for enzymes and other applications. The long-term goal of this project is to preserve >90 % bioactivity of a model protein, insulin, when released from PLGA MS and to achieve pseudozero-order release kinetics for more than one month period in in vitro and in vivo tests. The research specific aims include 1) experimental verification of optimized PEG-polyHis (or PEG-modified polyHis)/insulin complex for maximum insulin stability in aqueous solutions, in PLGA MS and during release, 2) a better control over release profile and 3) in vivo performance tests combined with biocompatibility and the fate of the diblock copolymer. ? ? ? ?
| Tian, Li; Kang, Han Chang; Bae, You Han (2013) Endosomolytic reducible polymeric electrolytes for cytosolic protein delivery. Biomacromolecules 14:2570-81 |
| Kang, Han Chang; Lee, Ji Eun; Bae, You Han (2012) Nanoscaled buffering zone of charged (PLGA)n-b-bPEI micelles in acidic microclimate for potential protein delivery application. J Control Release 160:440-50 |
| Taluja, Ajay; Bae, You Han (2008) Role of a novel multifunctional excipient poly(ethylene glycol)-block-oligo(vinyl sulfadimethoxine) in controlled release of lysozyme from PLGA microspheres. Int J Pharm 358:50-9 |
| Taluja, Ajay; Bae, You Han (2007) Role of a novel excipient poly(ethylene glycol)-b-poly(L-histidine) in retention of physical stability of insulin at aqueous/organic interface. Mol Pharm 4:561-70 |
| Taluja, Ajay; Bae, You Han (2007) Role of a novel excipient poly(ethylene glycol)-b-poly(L-histidine) in retention of physical stability of insulin in aqueous solutions. Pharm Res 24:1517-26 |
