Thesis
Novel devices for evaluating nanomedicine biological fate
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2024
- Thesis identifier
- T17066
- Person Identifier (Local)
- 201969528
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- The formation of the protein (biomolecular) corona around nanoparticles is a phenomenon of high current interest in pharmaceutical sciences, as the composition of the protein corona is known to influence nanoparticle biological fate. The protein corona can be modified by many physicochemical parameters, including the presence of fluid shear, leading to differences in both thickness and composition when results from static in vitro and dynamic in vivo studies are compared. This thesis considers the protein corona that develops around the biologically compatible poly (lactic-co-glycolic) acid (PLGA) nanoparticles following coincubation with biological media (foetal bovine serum, human serum) before moving on to study the physiological forces experienced by these nanoparticles in vivo immediately following the introduction into the body via several clinically used vascular access devices. This work presents (for the first time) the use of resonant mass measurement to analyse protein corona formation around submicron polymeric nanoparticles and shows its use as an orthogonal method alongside particle tracking analysis. Computational fluid dynamics (CFD) has been used to study blood flow in vivo. Finally, the insights obtained here were then used as input parameters to guide the design and development of a 3D-printed microfluidic device capable of subjecting nanoparticles to physiologically relevant fluid shear. This device will give rise to a protein corona with a structure and composition more like that obtained in vivo without requiring animal-based pre-clinical studies. In this work, it has been shown that there are statistically significant temporal, temperature and protein concentration effects on the composition of the protein corona around PLGA nanoparticles (0 vs 24hrs, p=<0.001, 25°C vs 37°C p=0.02, 10% FBS vs 20% FBS, p=0.01). With reference to previously published work, a combined CFD-DEM methodology has successfully been developed to study fluid flow and nanoparticle behaviour in vivo. Furthermore, additional insights were developed using principal component analysis to identify key physical parameters that influence protein corona formation. Finally, these were used to successfully develop a microfluidic device that is compatible with the manufacturing limits of fused deposition modelling and capable of replicating the physiologically relevant forces identified previously. Further study of this phenomenon would enable the data-driven prediction of nanoparticle characteristics from protein corona composition and/or biological fate, enhancing the translational success of novel nanotherapeutics from lab bench to patient bedside.
- Advisor / supervisor
- Brown, Cameron
- Johnston, Blair
- Resource Type
- DOI
Beziehungen
Objekte
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PDF of thesis T17066 | 2024-09-18 | Öffentlich | Herunterladen |