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Sunderland Repository records the research produced by the University of Sunderland including practice-based research and theses.

Development Of Biodegradable Polymeric Nanoparticles: Repurposing Pimozide For Targeted Glioblastoma Chemotherapy

Uddin, Nazim (2022) Development Of Biodegradable Polymeric Nanoparticles: Repurposing Pimozide For Targeted Glioblastoma Chemotherapy. Doctoral thesis, The University of Sunderland.

Item Type: Thesis (Doctoral)


Pimozide is a first-generation antipsychotic drug, which has also been reported as a potential chemotherapeutic candidate for glioblastoma, a fast-growing deadly brain cancer that is still quite difficult to treat with current clinical interventions. Repurposing pimozide for glioblastoma is not straightforward process since pimozide would induce its unwanted antipsychotic and related adverse side effects. Recently, nanomedicines are making outstanding progress in delivering new or existing therapeutics in targeted sites. However, there is a lack of studies that propose different approaches to repurpose pimozide in the form of nanomedicines. In fact, there is no study that has developed pimozide-nanomedicine targeting glioblastoma.
This thesis presents development of novel formulations of pimozide that could be applied as nanomedicine for glioblastoma targeted therapy. Formulations, in the form of nanoparticles, are composed of a biodegradable co-polymer, namely polylactide-co-glycolide (PLGA), which has been used as a safe drug delivery system for human. Nanoparticles were designed, prepared, and tuned to achieve desired physicochemical properties (particle size, size distribution, surface charge, and drug encapsulation efficiency) by exploring several process and formulation parameters, such as preparation methods (single emulsion-solvent evaporation and microfluidics), and formulation compositions (types and concentrations of excipients). In addition, an ultra-high-performance liquid chromatography method was developed and validated to analyse pimozide in the nanoparticles. Tuned PLGA nanoparticles were further functionalised (surface modified) with polyethylene glycol (PEG) and transferrin.
The key findings indicate that nanoparticles prepared by microfluidic method were significantly smaller and more efficient in entrapping pimozide than that of single emulsion-solvent evaporation method. Therefore, this study took the advantage of microfluidic method (and its tunable conditions) to further optimise the formulation. Tuned microfluidic conditions, based on the physicochemical properties of nanoparticles, were achieved at 12 mL/min (total flow rate) and 1:1 (flow rate ratio) of aqueous and organic phases. It was found that D-α-tocopherol polyethylene glycol 1000 succinate (TPGS)-stabilised nanoparticles were significantly smaller compared to the nanoparticles stabilised by other surfactants used in this study. In terms of PLGA concentration, results indicated that both particle size, anionic surface charge, and drug encapsulation efficiency were increased with the increase of PLGA concentration. It was also noticed that highly anionic PLGA nanoparticles became significantly less anionic after the surface modification with PEG and transferrin. Thus, this study achieved an optimised formulation with small particle size (<100 nm), narrow size distribution (polydispersity index of ≤0.3), anionic surface charge (zeta potential value of -10 to -18 mV), and high pimozide encapsulation efficiency (47-73%), which are ideal properties for drug delivery to the brain by intravenous administration. Furthermore, results suggested that targeted nanoparticles in suspension remained stable up to 4 months at 4ºC of temperature. Western blot analysis confirmed the expressions of transferrin receptors on glioblastoma cell lines E2, G7, and R24, supporting other studies with different glioblastoma cell lines. Finally, by cell proliferation assay, an effective inhibition concentration of pure pimozide was found to be 5 µM, which also supported previous studies. However, the effective concentration at which pimozide-loaded PLGA nanoparticles inhibited glioblastoma cell growth was achieved at 10 µM. In addition, it was found that the targeted nanoparticles significantly inhibited the growth of glioblastoma cells than that of non-targeted nanoparticles. Therefore, this study suggests that pimozide, once encapsulated within biodegradable PLGA nanoparticles, could be repurposed for targeted glioblastoma treatment.

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NU PhD Thesis for library (Nazim Uddin)-February 2022.pdf - Accepted Version
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Depositing User: Delphine Doucet


Item ID: 17203

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Date Deposited: 08 Jan 2024 14:33
Last Modified: 08 Jan 2024 14:45


Author: Nazim Uddin

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Collections > Theses


Sciences > Biomedical Sciences
Sciences > Health Sciences

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