The development and characterisation of MicroRNA and gemcitabine nanotherapies for the treatment of pancreatic cancer

Abstract

Pancreatic cancer has been considered as the most lethal cancer type among adults for many decades. Especially with the failure to improve survival rates for the last 40 years, despite all the progress in targeting therapies. With the lack of therapeutic options, attention has been directed towards innovative platforms in a bid to overcome the resistant and aggressive nature of the disease.

Micro-RNAs are endogenous small, non-coding RNAs considered to be post-translational regulators for the expression of targeted genes. The utilization of miRNAs as therapeutic agents has showed promising rapid progress in the last 10 years but are limited because of the lack of appropriate delivery systems that will ensure reach of the pharmacological targets. On the other hand, the bottleneck with using gemcitabine, the first line chemotherapeutic agent, is the rapidly developing resistance coupled with low bioavailability.

The aim of this project is to elucidate the potential role of miR-143, miR-145 and gemcitabine triphosphate in the treatment of pancreatic cancer when delivered in fusogenic peptide-based nanoparticles.

To date, results have shown that the fully characterised nanoparticles can transfect pancreatic cell lines with efficient delivery of the cargo intracellularly, as detected by FACS and qRT-PCR analysis. The restoration of miR-143 and miR-145 demonstrated disruption in BxPC-3 functionality while no response was observed with MIA-PaCa2. On the other hand, PANC-1 had variable responsiveness to both miRNAs which highlights the significant role of cellular variation and
molecular signature on the effectiveness of miR-143/145 as a therapeutic option.

In contrast, administering gemcitabine triphosphate via the developed nanoparticles resulted in consistent efficacy among the cell lines suggesting a common mechanism of evading gemcitabine resistance and intraindividual variability. Furthermore, RALA/GTP nanoparticles demonstrated potentiation of the cytotoxic effect of the chemotherapeutic agent by 8- to 24-fold compared to the parental drug.

Thesis embargoed until 31 July 2027.

Date of Award	Jul 2022
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	Helen McCarthy (Supervisor), Ryan Donnelly (Supervisor) & Ahlam Ali (Supervisor)