Search

Amphiphilic block co-polymers composed of poly(ethylene glycol)-co-poly(lactide)-co-poly(2-((tert-butoxycarbonyl)amino)-3-propyl carbonate) (PEG-pLA-pTBPC) are synthesized in monomer ratios and arrangements to enable assembly into nanoparticles with different sizes and architectures. These materials are based on components in clinical use, or known to be biodegradable, and retain the same fundamental chemistry across 'AB' and 'BAB' block architectures. In MCF7 and MDA-MB-231 breast cancer cells, nanoparticles of < 100 nm are internalized most rapidly, by both clathrin-and caveolin-mediated pathways. In THP-1 cells, polymer architecture and length of the hydrophilic block is the most important factor in the rate of internalization. The organ distributions of systemically injected nanoparticles in healthy mice indicate highest accumulation of the BAB-blocks in lungs and liver and the lowest accumulation in these organs of a methoxyPEG5000-pLA-pTBPC polymer. Conjugation of doxorubicin via a serum-stable urea linker to the carbonate regions of PEG5000-pLA-pTBPC generates self-assembling nanoparticles which are more cytotoxic in 2D, and penetrate further in 3D spheroids of triple negative breast cancer cells, than the free drug. In an aggressive orthotopic triple negative breast cancer mouse model, the methoxyPEG5000-pLA-pTBPC is of similar potency to free doxorubicin but with no evidence of adverse effects in terms of body weight.

Glioblastoma multiforme (GBM) (recently classified by the World Health Organisation as glioblastoma isocitrate dehydrogenase wild-type or mutant), is the most common, malignant brain tumour in adults, mainly due to its rapid proliferation and ability to penetrate and diffusely infiltrate healthy brain parenchyma. Standard of care treatment consists of surgical debulking of the tumour, followed by an intense course of concomitant chemotherapy and radiotherapy. However, despite these multimodal treatment methods, and a greater understanding of disease biology, prognosis remains bleak with a median survival of 14 months from diagnosis. \ud \ud This front-line treatment whereby tumours are neurosurgically-resected, poses a distinct opportunity for the consideration of localised, intracranial therapy for GBM patients, hereby overcoming the blood-brain barrier (BBB) and enabling the delivery of therapeutics directly to the site of the infiltrative disease left behind following surgical resection. The overarching aim of this thesis is to design and synthesise drug-loaded nanocarriers which can be incorporated into a pre-existing microparticulate paste to act as a localised drug delivery system for the treatment of GBM.\ud \ud Chapter 2 details the design and synthesis of a library of these drug-loaded nanocarriers, optimising an established ring-opening polymerisation (ROP) method to enable a user-friendly approach with a fast reaction time, resulting in polymers with highly predictable final molecular weights and narrow molar mass dispersities (Đ). The introduction of a functionalisable monomer enabled the conjugation of doxorubicin (DOX), a relevant chemotherapeutic, to the polymeric backbone. The resultant polymers were able to reproducibly self-assemble to form kinetically-trapped nanoparticles (NPs) with narrow polydispersity indexes (PDIs).\ud \ud Chapter 3 details the cytotoxicity of the DOX-NPs on a range of GBM cell lines. Considering the inevitable recurrence of GBM is due to the infiltrative cells left behind following surgical removal of the original tumour, the NPs were tested upon a range of patient derived cell lines isolated from this infiltrative region, allowing a more clinically-relevant insight into the activity of the formulations. \ud \ud Overall, the results from this thesis highlight the potential of incorporating drug-loaded NPs into a pre-existing microparticulate paste, for the first time in neuro-oncology, building a platform technology for future in vivo studies to investigate the potential efficacy of this delivery system as a localised treatment method for GBM.