The manufacture of implantable drug delivery devices for the localised treatment of brain tumours

Abdelnabi, Dina Mohammed Ibrahim Metwalli ORCID: 0000-0002-8239-9881 (2023). The manufacture of implantable drug delivery devices for the localised treatment of brain tumours. University of Birmingham. Ph.D.

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Abstract

High-grade gliomas (HGGs) have a poor prognosis (<15 months with current treatment) and often recur both at, but also beyond, the surgical margins, making total removal challenging. The blood-brain barrier (BBB) substantially limits therapeutic drug levels to these cells. This study discussed the development of irinotecan hydrochloride (IRN) and infigratinib (INF)-loaded poly (lactic-co-glycolic acid) (PLGA) ChemoSeeds using hot-melt extrusion (HME) for implantation into the glioblastoma (GBM) resection cavity margin directly after surgery to deliver a sustained high local dose of chemotherapy with less systemic toxicity.

First, rheological studies were conducted to identify micro-extrusion and HME processing temperatures to produce IRN ChemoSeeds. ChemoSeeds with various IRN loadings, different plasticiser types and concentrations were prepared and characterised for content uniformity, IRN distribution using Raman mapping, IRN solid-state using DSC and XRD, and in-vitro IRN release. We found that the IRN and plasticiser loadings altered the in-vitro %release and that HME improved IRN ChemoSeed's content uniformity, IRN distribution, and solubility within the PLGA.

We then demonstrated that HME without a plasticiser produced PLGA5004-loaded IRN ChemoSeeds with good critical quality attributes (CQAs). The use of Box-Behnken Design (BBD) to study the effects of the critical process parameters (CPPs) (feed rate, screw speed, temperature) for the formulation of 30% and 40% w/w IRN ChemoSeeds on the CQAs (weight, diameter, content uniformity, and in-vitro release on day 7) was demonstrated. In vivo toxicity study indicated necrosis in the implantation site of ChemoSeeds loaded with 30% and 40% w/w IRN on days 45 and 14, respectively. There was no systemic toxicity with 30% or 40% w/w IRN-loaded ChemoSeeds. After receiving 30% w/w IRN-loaded ChemoSeeds, 80% of mice survived to day 148 without tumour recurrence, whereas all mice in the 40% group died by day 70. These results showed the 30% w/w IRN-loaded ChemoSeeds are a promising treatment for HGGs that might be rapidly transferred into the clinic.

Next, we formulated and characterised INF-loaded PLGA5004 ChemoSeeds at loadings between 10 and 50% w/w for content uniformity, INF solid-state characterisation, INF distribution, and in-vitro INF release. In vivo toxicity study showed no signs of local or systemic toxicity with 20%, 30% and 40% w/w INF ChemoSeeds, making them ready to undergo an in vivo efficacy study using a patient-derived xenograft model of GBM.

Finally, we developed IRN-loaded 3D printed (3DP) dosage forms using PLGA5004 filaments with various IRN loadings. The printability of filaments was measured with a three-point bending test. In-vitro drug release was shown to be related to the Surface area/volume (SA/Vol) ratio. The 3D printed implant and the 6mm tablet with 25% infill had the highest SA/Vol ratio and near-zero release kinetics. This study is considered the first Fused-Deposition Modelling (FDM) 3D printing attempt of IRN/PLGA5004 dosage forms for customised drug release and a massive step toward 3D printing biodegradable PLGA single- and multi-layered brain implants.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):