Development of novel implantable hydrogels and aerogels for localised cancer treatment

Alsharif, Shaker (2023). Development of novel implantable hydrogels and aerogels for localised cancer treatment. University of Birmingham. Ph.D.

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Abstract

Pancreatic and bladder cancers are common types of cancer and related to a considerable rate of morbidity and mortality if not managed properly. The adjuvant chemotherapy following the surgical tumour resection is required for both cancer types in order to eliminate any remaining malignant cells to prevent cancer metastasis. Hydrogels and aerogels are promising strategies that can be designed and used to improve the drug delivery into the pancreas and bladder. In the first study, caffeine-loaded agar hydrogels, pre- and post-loaded aerogels were developed as potential implantable drug delivery systems. Several hydrogel and aerogel formulations were prepared by either sol-gel or post-loading methods using increasing concentrations of agar polymer and caffeine as model drug. These two variables were investigated for their impacts on hydrogels and aerogels physical properties, drug content homogeneity and release profiles to determine the optimized formulations. Irinotecan Hydrochloride (IRN)-loaded agar hydrogels pre- and post-loaded aerogel formulations were developed using the optimized formulations as implantable drug delivery systems to improve IRN delivery to the tumour resection sites and increase their efficacy as post-surgical localised treatment for pancreatic cancer. The formulations variables based on the amount of agar and IRN were investigated for their effects on the hydrogels and aerogels physical properties, drug content distribution and release profiles, as well as their cytotoxicity using different pancreatic cancer cell lines. The IRN-loaded hydrogels and aerogels showed stronger mechanical strength and lower levels of hydrogel adhesion, as well as IRN distribution for both formulations with higher agar concentration, while better IRN distribution and more flexible aerogels were associated with lower agar concentration. The in vitro release of IRN from all hydrogel and aerogel formulations demonstrated concentration dependent prolonged release over 4 days. The
hydrogels and preloaded aerogels showed faster sustained release rate as the agar concentration decreased due to the increased porosity, while post-loaded aerogels demonstrated slower release profiles as IRN loading rate decreased resulted from lower level of drug distribution. The
cytotoxicity assay of IRN pre- and post-loaded agar aerogels against MIA PaCa-2 cells demonstrated more time and concentration dependent reduced cell viability compared to their cytotoxic effect against Panc-1 cells. In the second study, the development of Infigratinib (INF)-loaded HEC and HPMC hydrogels was established to possibly enhance the INF delivery to the bladder through intravesical administration and potentially increase its efficacy as localised treatment of non-muscle invasive bladder cancer (NMIBC). Based on varying concentrations of HEC and HPMC polymers, as well as INF loading, several hydrogel formulations were prepared by sol-gel method. The effects of these varying concentrations on both sets of hydrogels rheological properties, drug content distribution and release profiles were assessed. The hydrogels with lower HEC and HPMC concentrations, as well as INF loading demonstrated reduced viscosity, suitable shear thinning behaviour making them easier to deliver through a catheter based the rheological analysis and injectability assessment. They showed acceptable drug content distribution. The INF-loaded
HEC hydrogels showed better concentration dependent mucoadhesive features compared to the INF-loaded HPMC hydrogels. The release of INF from the HEC and HPMC hydrogels showed a rapid ‘burst’ release associated with the low HEC and HPMC concentrations, as well as INF
loading over 24 hours, while as the HEC and HPMC concentrations and INF loading increased the percent release of INF from the hydrogels reduces. The cytotoxicity of the optimised INFloaded HEC hydrogel against FGFR mutant and non-mutant cancer cells demonstrated a similar cytotoxic effect to the free INF and selectively inhibited FGFR mutant cancer cells proliferation. Overall, the results demonstrate that the IRN-loaded agar hydrogels and aerogels have the potential to be effective for the post-operative localised treatment of pancreatic cancer. The targeted therapy using INF-loaded HEC hydrogel through intravesical administration is promising for NMIBC cases associated with FGFR mutations.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):