Dissertation
STOCHASTIC MODELING AND SIMULATIONS OF TARGETED DRUG DELIVERY ACROSS BLOOD-BRAIN BARRIER USING NANOPARTICLES
Doctor of Philosophy (PhD), Washington State University
01/2019
Handle:
https://hdl.handle.net/2376/112258
Abstract
The existence of the blood-brain barrier (BBB) makes the treatment of brain diseases and cancers significantly challenging. The BBB strictly regulates the transport of molecules from the blood side into the brain parenchyma. Delivery of drug-loaded nanoparticle (NP) across BBB through receptor-mediated transcytosis (RMT) has been a promising strategy to overcome the obstacle. But the optimal design of nanoparticle for effective delivery across BBB is still a daunting task. The successful transport of nanoparticles across BBB through RMT is a complex and multi-stage process. The understanding of the mechanism of RMT is critical for the future drug delivery system.
Firstly, the designed nanoparticle should be internalized at the blood side through endocytosis. Among which, the receptor dependent clathrin-mediated endocytosis (CME) is one of the most important pathways for the delivery of nanoparticles. In our study, we have built a stochastic computational model to investigate the CME based on Metropolis Monte Carlo simulations. The model systematically incorporates the ligand-receptor interactions, development of clathrin-coated pit (CCP) and membrane deformation during the CME. We also studied the influences of key designing parameters such as particle size and ligand density as well as membrane mechanical property on the CME.
Secondly, to effectively deliver NPs across BBB, it is important not only enter the cell from the blood side but also release the cargo on the brain side. Different from CME, the exocytosis is proposed to be strongly regulated by the activity of actin filaments. Therefore, we developed a model for the exocytosis by considering the effect of actin tension and force. Combining the CME and exocytosis models together, we studied the overall impact of designing parameters on the whole transcytosis.
Lastly, though most current nanocarriers designed in lab and clinical trials are spherical, the advancing of nanofabrication techniques enables the manufacturing of various shaped nanoparticles mimicking the viruses and bacteria in nature. The designing of nonspherical nanoparticle is of significant meaning for the future drug delivery system. Therefore, we extended our model to investigate the designing factors and overall transcytosis effectiveness of ellipsoidal nanoparticles in comparison to its spherical counterparts.
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Details
- Title
- STOCHASTIC MODELING AND SIMULATIONS OF TARGETED DRUG DELIVERY ACROSS BLOOD-BRAIN BARRIER USING NANOPARTICLES
- Creators
- Hua Deng
- Contributors
- Jin Liu (Advisor)Prashanta Dutta (Committee Member)Soumik Banerjee (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- School of Mechanical and Materials Engineering
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 166
- Identifiers
- 99900581505301842
- Language
- English
- Resource Type
- Dissertation