ULTrasound-controlled delivery technologies for IMproving oral drug Absorption, Targeting and Efficacy (ULTIMATE)

点击翻译按钮获取中文摘要

Ultrasound has shown potential to enhance buccal and rectal drug delivery through transient disruption of the barrier; however, its application in oral delivery remains largely unexplored. This innovative project will investigate the use of ultrasound stimulation, in combination with stimuli-responsive drug carriers, as a non-invasive physical intervention to reversibly disrupt the gut wall enabling spatially and temporally controlled permeation of oral APIs across biological barriers throughout the gastrointestinal tract (GIT). It is anticipated that this approach will significantly improve systemic absorption in general/specific patient populations (e.g., paediatric, geriatric, IBD). Biologics offer promising treatments for a wide array of diseases due to their target specificity, greater efficacy and less off-target side effects compared to small molecular weight drugs. Although oral administration of these compounds is preferred to parenteral routes, development of oral biologic formulations has been hindered by their high molecular weight, limited stability and half-life, and poor epithelial permeability. For example, IBD patients have high morbidity and compromised quality of life whose treatment options include intravenous biologics (e.g., adalimumab), given at high doses to achieve therapeutically relevant mucosal levels. However, this approach can lead to loss of efficacy and development of immunogenic side effects. Local delivery of biologics via oral administration would facilitate lower doses with potentially higher efficacy and a reduced side effect profile. Despite almost a century of research and recently renewed efforts, oral biologics are still absent in the clinical setting. This highlights the significant challenges posed by the GIT barrier to their oral delivery, as well as associated inter-patient variability issues. Established chemical absorption enhancer strategies have demonstrated in vitro success, but a lack of clinical translation due to difficulties in co-localising biologic payload and enhancers. Therefore, in the proposed research we intend to overcome these difficulties, by exploiting ultrasound as a means of localising and actively controlling drug release from carriers by remote stimulation, whilst enhancing drug penetration through the GIT barrier. Ultrasound exposure could thus increase permeation of macromolecules while allowing co-localisation of stabilising excipients and macromolecular payloads. Ultrasound is a longitudinal pressure wave with frequencies above the upper audible limit (>20kHz). It has been applied in a variety of clinical settings, including ultrasonography, tumour ablation and lithotripsy. More recently, it has been investigated in therapeutic applications as a physical means to transiently permeabilise biological tissues and enhance penetration of bioactive compounds. In these applications, it is often applied in combination with ultrasound-responsive agents (e.g., shelled gas microbubbles or volatile nanodroplets), which can be engineered to carry different classes of bioactive and targeting moieties for localised delivery. Upon exposure to ultrasound waves, these agents undergo volumetric oscillations imparting mechanical stress on nearby biological barriers and improving transport of therapeutic payloads, thus representing a highly promising candidate system for targeted oral delivery of biologics. Moreover, by varying the characteristics of the ultrasound field (e.g., amplitude and frequency), the intensity and mode of particle response could be modulated to meet patient- or disease-specific needs. In this project we will first re-engineer current ultrasound-sensitive particle formulation and manufacturing strategies to enable effective loading of biologics. We will then assess their performance in vitro and ex vivo under patient-/disease-specific gastrointestinal exposure conditions, to customise the developed formulations.