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

超声显示出通过短暂破坏口腔和直肠屏障来增强口腔和直肠药物输送的潜力；然而，它在口服给药中的应用在很大程度上仍未被探索。这个创新的项目将研究使用超声刺激，结合刺激反应性药物载体，作为一种非侵入性的物理干预，可逆地破坏肠壁，使口服原料药在空间和时间上控制穿透整个胃肠道（GIT）的生物屏障。预计这种方法将显著改善一般/特定患者群体（如儿科、老年、IBD）的全身吸收。与小分子量药物相比，生物制剂由于其靶向特异性、更高的疗效和更少的脱靶副作用，为广泛的疾病提供了有希望的治疗方法。尽管口服给药优于肠外给药，但口服生物制剂的开发一直受到其高分子量、有限的稳定性和半衰期以及上皮渗透性差的阻碍。例如，IBD患者发病率高，生活质量受损，其治疗选择包括静脉注射生物制剂（如阿达木单抗），以达到治疗相关的粘膜水平。然而，这种方法可能导致疗效的丧失和免疫原性副作用的发展。通过口服政府将局部递送生物制剂有助于降低剂量，潜在的更高疗效和更少的副作用。尽管近一个世纪的研究和最近的新努力，口服生物制剂在临床环境中仍然缺席。这突出了胃肠道障碍对其口服递送的重大挑战，以及相关的患者间变异性问题。已建立的化学吸收增强剂策略在体外取得了成功，但由于生物有效载荷和增强剂的共定位困难，缺乏临床转化。因此，在我们提出的研究中，我们打算克服这些困难，利用超声作为一种手段，通过远程刺激来定位和主动控制药物从载体中释放，同时增强药物穿透GIT屏障。因此，超声暴露可以增加大分子的渗透，同时允许稳定赋形剂和大分子有效载荷的共定位。超声波是一种纵向压力波，频率高于可听上限（> - 20kHz）。它已应用于各种临床设置，包括超声检查，肿瘤消融和碎石。最近，它作为一种物理手段在治疗应用中被研究，以瞬时渗透生物组织和增强生物活性化合物的渗透。在这些应用中，它通常与超声响应剂（例如，有壳气体微泡或挥发性纳米液滴）结合使用，可以设计成携带不同类别的生物活性和靶向部分，以进行局部递送。暴露于超声波后，这些药物会发生体积振荡，对附近的生物屏障施加机械应力，并改善治疗有效载荷的运输，因此代表了一种非常有前途的靶向口服生物制剂候选系统。此外，通过改变超声场的特性（例如振幅和频率），可以调节粒子响应的强度和模式，以满足患者或疾病的特定需求。在这个项目中，我们将首先重新设计当前的超声敏感颗粒配方和制造策略，以实现生物制剂的有效装载。然后，我们将在患者/疾病特异性胃肠道暴露条件下评估其体外和离体性能，以定制开发的配方。

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.