Abstract
As populations age worldwide, neurological diseases and disorders have emerged as leading causes of global morbidity and mortality. Despite significant advances in treatment, including surgical and radiation therapies, therapeutic options remain limited, often requiring invasive, non-localized and resource-intensive interventions placing a substantial burden on the patients and the healthcare system. Drug delivery and other non-invasive treatment approaches are often hindered by the brain's protective layers, presenting a major obstacle to therapeutic efficacy.
Systemic injections of drugs often deliver only minor fractions of the administered dose to the targeted pathology, resulting in unwanted toxicity towards healthy tissue. In brain tissue, drug delivery is impaired by the highly selective nature of the blood brain barrier (BBB) impeding the influx of most substances. Thus, there is a significant unmet medical need for novel therapeutic approaches that enable targeted delivery to affected regions of the brain.
Focused ultrasound combined with microbubbles has emerged as a promising transformative approach, either as an alternative or a complement to conventional therapies for neurological diseases and disorders. This approach offers a localized, non-invasive and potentially cost-effective method for delivering therapeutic agents across the BBB to the targeted site.
Conventional ultrasound contrast agents, originally developed for diagnostic imaging, are frequently used to enhance drug delivery; however, they present several limitations for therapeutic applications. As a result, microbubble platforms specifically engineered for therapeutic applications have been developed. Acoustic Cluster Therapy (ACT), developed by EXACT Therapeutics, is a technology platform for targeted therapeutic enhancement with the potential to significantly amplify the clinical utility of a wide range of therapeutic agents across a multitude of indications. The technology is based on a combination of intravenously injected PS101 microclusters, followed by ultrasound application creating oscillating ACT bubbles that increase the accumulation and therapeutic efficacy of systemically administered therapeutic agents at the target site. Compared to conventional microbubbles, ACT is anticipated to produce distinct biomechanical effects, primarily due to the ACT bubbles’ larger volume, covering a larger area within the capillaries and maintaining closer contact with the endothelium.
ACT has shown an increased therapeutic efficacy in several preclinical abdominal cancer models across different cancer drugs as well as a in a first clinical trial in patients with liver metastases. The aim of this thesis was to further elucidate and strengthen the understanding of the overall mechanism of ACT and to explore the potential of ACT for localized drug delivery to the brain. Mechanistic studies included in the thesis revealed spherical and ellipsoidal ACT bubbles within the vasculature, ranging from 7 to 66 μm in diameter, depending on the model system. Oscillations of ACT bubbles revealed an absolute radial expansion of 1-2 μm, accompanied by transient changes in vascular diameter and fluorescence intensity within the vasculature. Both rapid and slow extravasation events, spanning 1- 50 s in the model systems, were observed, originating from saccular outpouchings in the brain capillaries. ACT bubbles safely and transiently increased BBB permeability, resulting in a 3.7-fold enhancement in the accumulation of clinically relevant core-crosslinked polymeric micelles demonstrating the potential of ACT for localized drug delivery to the brain.