Development of irinotecan hydrochloride loaded PLGA nanoparticles for the treatment of glioblastoma

Al Amri, Ali (2021). Development of irinotecan hydrochloride loaded PLGA nanoparticles for the treatment of glioblastoma. University of Birmingham. Ph.D.

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Abstract

Glioblastoma multiforme (GBM) is one of the most aggressive and deadliest types of tumours in both adults and children. The difficulty of delivering drugs to the brain is a major obstacle in the treatment of GBMs. Nanoparticles (NPs) are a promising strategy that can be designed to improve drug delivery to the brain. In this study, Irinotecan Hydrochloride (IRN)-loaded poly(lactide-co- glycolide) (PLGA) NPs and IRN and Pitavastatin (PTV) co-loaded PLGA NPs were developed to improve their delivery to the brain and increase their efficacy as a treatment for GBM.

The IRN-loaded PLGA NPs were developed using a Box-Behnken design (BBD) study to investigate the effect of formulation variables on their critical quality attributes and prepared by the single emulsion solvent evaporation method. The formulation variables of the amount of IRN and PLGA, as well as the percent of Poly (vinyl alcohol) (PVA), were investigated for their impact on the physical properties of the NPs. The cytotoxicity, cellular uptake, and apoptotic effect of the IRN-loaded PLGA NPs was evaluated using primary GBM cells. The ability of the NPs to cross the blood brain barrier (BBB) was investigated using a cerebral microvascular endothelial cell line D3 (hCMEC/D3) monolayer BBB model and hCMEC/D3 cells with astrocytes multilayer BBB model. The permeability of the BBB was determined using the transendothelial electrical resistance (TEER) value. TEER values in the monoculture BBB model were measured using EVOM2 and ECIS, while cellZscope was used to measure the TEER values with the co-culture BBB model. The optimised IRN-loaded PLGA NPs showed a nearly spherical shape with particle sizes ranging from 150 - 300 nm, a polydispersity index (PDIs) less than 0.3, zeta potentials of -10 to -30, and EEs ranging from 40.8 to 88.94 depending on the formulation and type of PLGA (5002 and 5004). PLGA 5002 had the highest EE due to it being acid terminated resulting in an electrostatic interaction with the HCL group of the IRN. The in vitro drug release demonstrated a prolonged release over 9 days with a maximum of 40% released from the 5002 NPs, and 85% from the 5004 NPs. The lower level of IRN release from 5002 was due to the electrostatic interaction. The release of the IRN was much higher in acidic media compared to the normal pH. All of the optimised NPs were shown to have comparable cytotoxicity to the free IRN at 1 and 10 µM as well as reducing the TEER value of the mon- and co-culture BBB models, which suggests their ability to cross the BBB. The optimised NPs were able to internalize in the primary GBM cells and their cellular uptake was time and concentration dependent.

Three different formulations of the IRN and PTV co-loaded NPs (C1, C2, and C2) were developed and characterised for their size, zeta potential, PDI, EE, and drug release. The C2 NPs were chosen for evaluation of their cytotoxicity and cellular uptake using primary GBM cells as well as their ability to cross BBB models (mono- and co-culture BBB models). The size of the C2 NPs was 70 nm with a PDI of 0.21, while the EEs of the IRN and PTV were 44.56 and 18.50%, respectively. The C2 NPs were shown to be cytotoxic against primary GBM cells and were able to cross the mono- and co-culture BBB models. Overall, the results demonstrate that the IRN-loaded as well as the IRN and PTV co-loaded PLGA NPs have the potential to be an effective treatment for GBM.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):