Development of novel combinational implants for the localised treatment of brain tumours

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Lastakchi, Sarah ORCID: https://orcid.org/0000-0003-4644-0928 (2020). Development of novel combinational implants for the localised treatment of brain tumours. University of Birmingham. Th.D.

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Abstract

This thesis will show the discovery of two highly potent multidrug treatments against Glioma brain tumour and their subsequent development into an implantable drug delivery device.
Glioblastoma is a highly malignant cancer with fewer than 10% of patients surviving longer than 5 years. Initially through using patient derived primary tissue we have demonstrated that at low dose (<100 μM) repurposed drug treatments such as Pitavastatin, Irinotecan and Celecoxib are more effective than the current standard of care, Temozolomide. Of the 14 Glioma patients, only one (7 %) responded to Temozolomide, while 8 (57 %), 11 (79 %) and 12 (86 %) responded to Irinotecan, Pitavastatin and Celecoxib, respectively. We then examined drugs that had evidence of enhanced antitumor activity when combined, and two multi drug treatments were discovered. The first drug combination consisted of Irinotecan, Pitavastatin, Disulfiram and Copper Gluconate and the second combination was Irinotecan, Captopril and Disulfiram. Both were significantly more effective at killing Glioma cells and reducing reoccurrence than the individual drugs. To develop those two highly potent drug combinations into a pharmaceutical product, an analytical HPLC technique that is capable of separating, detecting and quantifying each drug within the implantable device was developed and subsequently validated for specificity, linearity, accuracy, precision, and robustness.
Finally, each drug combination was designed into a formulation. Rheology was performed to identify the most suitable matrix components, while swellability and DSC studies were used to measure implants physical and chemical stability. From all of the gathered data we have successfully formulated each of those multi-drug treatments into a novel multilayer drug delivery device, consisting of each drug incorporated homogeneously within either a 50:50 poly(lactic-co-glycolic acid) polymer or polymer plus Kolliphor® P 188 plasticiser additive, for the localised treatment of Glioblastoma.
In conclusion the significant cancer cell killing capability of Irinotecan-Pitavastatin-Disulfiram-Copper Gluconate and Irinotecan-Captopril-Disulfiram drug combinations as well as their successful formulation into a poly(lactic-co-glycolic acid) based drug delivery device demonstrates their future clinical translation potential and the need to continue further with product development and testing.

Type of Work:

Thesis (Doctorates > Th.D.)

Award Type:

Doctorates > Th.D.

Supervisor(s):