Abstract
Pharmacological strategies for managing Parkinson’s disease aim to alleviate disabling motor symptoms, primarily by dopamine supplementation using a prodrug (levodopa) or receptor agonist (e.g., ropinirole). However, the oral delivery of these drugs results in non-physiological dopaminergic stimulation at affected striatal nuclei and off-target effects that collectively lead to suboptimal drug efficacy and adverse drug effects. To circumvent this, our laboratory developed a drug delivery system that encapsulated ropinirole into liposomes and utilised targeted, transcranially applied, focused ultrasound to induce ropinirole release. Therefore, this system aims to enhance temporal-spatial control over ropinirole uptake, providing a novel, device-assisted method of drug delivery that may improve the long-term management of motor symptoms in PD. Stemming from this, we sought to adapt the use of focused ultrasound to disrupt the blood-brain barrier and eventually improve the delivery of anti-neoplastic therapeutics to brain tumours.
This thesis describes investigations into the efficacy and safety of a focused ultrasound-mediated drug release system aimed at improving the pharmacological management of Parkinson’s disease. These investigations were conducted via induction of a hemiparkinsonian rat model, followed by intravenous delivery of ropinirole-loaded liposomes in conjunction with ultrasound delivered by an extracranially implanted device. Subsequently, a ropinirole-induced, contralateral rotational motor response was assessed, and histological analyses were conducted to characterise efficacy and safety, respectively. Next, a pilot investigation adopting this focused ultrasound device for safe blood-brain-barrier disruption was conducted in rats by modifying ultrasound parameters and co-administering microbubbles. Subsequently, histological assessments characterised efficacy and safety outcomes.
Application of focused ultrasound following administration of ropinirole-loaded liposomes successfully induced ropinirole release, characterised by the commencement of significant contralateral rotational behaviour. However, this effect lacked complete reproducibility, citing heterogeneity in the in vivo stability of ropinirole-loaded liposomes. Following this, single and repeat applications of ultrasound did not induce significant blood-brain barrier disruption, nor any haemorrhagic, parenchymal, gliotic or apoptotic change. Additionally, upon coupling microbubble delivery with ultrasound applications, significant blood-brain barrier disruption was achieved, albeit with significant accompanying haemorrhagic, parenchymal, gliotic and apoptotic effects.
Blood-brain barrier disruption was also induced in rats through the co-administration of microbubbles and the application of focused ultrasound with modified parameters at varying peak negative pressures (0.32 – 1.06 MPa). At the lowest applied peak negative pressure (0.08 MPa), no significant blood-brain barrier disruption was observed. The extent of induced blood-brain barrier disruption increased significantly with escalating peak negative pressures. However, only with a peak negative pressure of 0.32 MPa was blood-brain barrier disruption achieved free of most adverse safety outcomes. Escalation of peak negative pressures was accompanied by increased haemorrhagic and parenchymal change, all of which correlated significantly. Gliotic and apoptotic change was only observed following blood-brain barrier disruption with a peak negative pressure of 1.06 MPa.
In summary, using an implantable device, we show proof-of-concept of a novel drug delivery system capable of safely releasing ropinirole from loaded liposomes upon application of transcranial focused ultrasound. Furthermore, we demonstrate the ability to adapt this ultrasound device to safely induce blood-brain barrier disruption by modifying parameters and co-applying microbubbles.