Date of Award

Summer 2018

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Zebunnissa Ramtoola

Second Supervisor

Dr Sarah O’Neill

Keywords

Nanoparticles, PLGA-PEG, Platelet Activation, Platelet Aggregation

Abstract

Particles at nanoscale levels have a potential for interacting at molecular and cellular levels. The expansion of nanotechnology, for drug delivery applications, has posed questions regarding their safety profile. Such issues are associated with the small size ranges, and the presentation of surfaces with unique physicochemical properties. To date, the effects of the interaction of nanoparticles (NPs) with blood constituents, in particular, platelets remain unclear.

In this study, the effects of the biodegradable PLGA-PEG NPs’ interactions with platelets were explored. NPs were formulated by a nanoprecipitation technique. A design of experiments approach was applied to investigate and model the interactive effect of pivotal formulation variables on the physical properties of NPs.

NPs of 100 - 600 nm average diameters were produced, with variable degrees of monodispersity and zeta potential values. Regression analysis proved that polymer concentration was the key factor governing NP size and aggregation. The nanoformulations were dried using spray drying and freeze drying. The latter was seemingly a more efficient tool in the recovery of NPs. Morphological characterisation of dry NPs, using scanning electron microscopy, revealed spherical NPs. Through thermal analysis, the moisture-free NPs seemed of similar thermal properties to the unprocessed polymer. Stability studies of NPs suggest a reasonable preservation of PS over 14 days.

The achievement of producing NPs of different sizes allowed for exploring the influence of PS on platelets. Changes in platelet function were examined using light transmission aggregometry, flow cytometry, and confocal microscopy. The NPs interfered with normal platelet aggregation profile in a size- and concentration-dependent manner. Also, washed platelet activation was enhanced with the smallest investigated NPs. Importantly, NPs bound to platelets, in both their resting and stimulated states.

This thesis presents data that contributes to a greater understanding of the haematocompatibility of engineered PLGA-PEG NPs in relation to platelets. It highlights the possibility that at specific concentrations and sizes, they might present potential vehicles for therapeutics targeted to platelets, for the clinical management of cardiovascular diseases.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

6.96

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2018.

Available for download on Saturday, May 30, 2020

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