The development of biodegradable nanoparticles for the systemic treatment of brain tumours

Mahmoud, Basant Salah Abdelmoneam (2022). The development of biodegradable nanoparticles for the systemic treatment of brain tumours. University of Birmingham. Ph.D.

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Abstract

The blood brain barrier (BBB) is a complex entity that restricts therapeutics from accessing the brain environment and reaching tumours in therapeutic doses. Development of polymeric nanoparticles (NPs) loaded with therapeutics could enhance the efficacy of the treatment. Polycaprolactone (PCL) is a biocompatible polymer that has a long-term degradation profile and does not lead to the production of acidic toxic products upon degradation. The aim of this thesis was to develop PCL NPs and PCL-PLGA blend NPs loaded with irinotecan hydrochloride (IRH) that can cross the BBB without impairing its integrity and be cytotoxic to high-grade glioma (HGG) cells. The results indicated that polymer amorphization and addition of electrolytes have resulted in enhanced encapsulation efficiency (EE) by the double emulsion solvent evaporation technique while maintaining the size of the NPs within an acceptable limit (<500 nm). By using Box-Behnken design (BBD) of experiments for further optimization, the most optimum conditions for producing the smallest size, lowest charge and highest EE% of PCL NPs were predicted to be achieved by using 61.02 mg PCL, 9 mg IRH and 4.82% PVA, which would yield 203.01 nm, -15.81 mV and 82.35% EE. Similarly, an optimum level of dependent factors of PCL-PLGA blend NPs would be achieved by using 162 mg polymer blend, 8.37 mg IRH and 8% PVA which would yield NPs with a size of 283.06 nm, a charge of -31.54 mV and a 70% EE. Blending PCL with PLGA has resulted in a reduced crystallinity and enhanced release of 69.39 ± 0.58 % over 16 days. Biological characterization of the NPs has revealed their haemocompatibility and their dose dependent cellular uptake in both HGG cells and endothelial cells. Additionally, the NPs were more cytotoxic than the free drug against HGG primary cells obtained from 3 different patients, where they induced apoptosis via the extrinsic pathway. In the endothelial cells, the NPs were able to cross the BBB and impose a less cytotoxic effect on their viability compared to HGG cells. By analysing the expression of interleukin-6 (IL-6) as a marker of immunogenicity, both HGGs and endothelial cells treated with the NPs had less expression of IL-6 as compared to the free IRH. In conclusion, manipulating the formulation parameters could help design NPs with desirable properties able to cross the BBB and treat malignant brain tumours while reducing the toxic side effects produced by free chemotherapies.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):