Development and characterisation of a peptide : bisphosphonate nanoparticle for the treatment of breast cancer
Queen's University Belfast, 2022
Online
Hochschulschrift
Zugriff:
In women, breast cancer (BC) is the most common cancer and despite improvements in long-term outcomes, recurrence is still significant. Unfortunately, metastatic disease is incurable with only 26% of BC patients reaching a 5-year survival rate. Bisphosphonates (BPs) are potent inhibitors of bone resorption and extensively used for the prevention and treatment of secondary bone cancer in BC patients. BPs not only act to inhibit osteoclast activity, but a growing body of evidence points towards an important anticancer effect not only in the bone metastatic niche but also at the primary tumour. In vitro data is promising, however high doses are required that are not physiologically achievable due to associated side effects The focus of this thesis was to repurpose the nitrogen-containing bisphosphonate (N-BP), Risedronate (RIS), into a novel anticancer therapeutic through complexation with the RALA peptide. The RALA peptide delivery system complexes anionic compounds through electrostatic interactions, to form nanoparticles (NPs) with the physiochemical characteristics to cross cellular membranes and escape endosomes; thereby releasing the cargo intracellularly to exert the optimal therapeutic effect. Here we report highly stable NPs formed with Risedronate (R-RIS NPs), that portrayed superior direct anti-tumour effects in vitro and in vivo in BC models, compared to RIS administered alone. Molecular studies showed R-RIS NPs were on target within the cell, inhibiting the main mechanism of action of N-BPs, known as the mevalonate pathway. Anti-tumour effects were confirmed with subsequent increased cytotoxicity and apoptotic cell death following R-RIS NP treatment, and inhibition of the AKT cell survival pathway compared to untreated and RIS alone. Furthermore, utilizing two in vivo models (MDA-MB-231 and 4T1), R-RIS NP treatment significantly reduced tumour growth, prolonged survival, increased tumour doubling times and prevented visceral metastasis of the primary tumour to the lungs. Biodistribution studies showed significantly more drug accumulation in the tumour with RALA delivery, and significantly higher accumulation still evident three weeks post administration. This thesis has demonstrated the characterisation of a novel therapeutic strategy in-cooperating the FDA-approved N-BP Risedronate into the RALA delivery system. R-RIS NPs presents great potential to improve treatment for early-stage BC (ESBC) by inhibiting primary tumour growth and preventing distant metastasis.
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Development and characterisation of a peptide : bisphosphonate nanoparticle for the treatment of breast cancer
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Autor/in / Beteiligte Person: | Glass, Kimberley ; Buckley, Niamh ; McCarthy, Helen |
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Veröffentlichung: | Queen's University Belfast, 2022 |
Medientyp: | Hochschulschrift |
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