Bubble Therapy: a New Paradigm for Targeted Drug Delivery by Ultrasound

在组织中传播的高振幅超声波最近被报道可以诱导一系列潜在的有益现象，如组织快速加热，增加细胞对大分子药物的渗透性（声孔效应）或增强药物的活性。这些生物效应与超声诱导的微米级气泡的成核和随后的激发密切相关，产生两种类型的声空化活动：(1)惯性空化，它极大地增加了向组织的能量传递，并可能导致快速加热和机械损伤；(2)稳定空化，气泡作为微泵，极大地增强了药物分子的局部混合和运输长度尺度。在癌症治疗中，局部加热与化疗相结合将使癌细胞对治疗更敏感，而局部微泵药物可以帮助克服由高度复杂的肿瘤结构引起的输送问题。在脑卒中治疗中分解血凝块的过程中，空化增强混合将促进药物传递到低血流量部位，并大大增加溶栓药物在血栓表面的扩散。然而，空化微泡的成核以及随后在生物相关介质中与细胞的相互作用仍然知之甚少。因此，拟议研究的目标是：(i)利用目前正在开发的用于分子成像的商业上可用的靶向纳米颗粒，研究细胞和部位特异性空化成核的潜力；（ii）了解和优化超声和空化可以增强局部药物传递和药物活性的机制，使其能够跨越肿瘤或血块等难以接近的界面；（iii）开发临床相关的监测空化活动的手段，并利用它们实时监测药物输送；（iv）在临床相关的器官模型中测试优化的药物输送和治疗监测方案。希望本研究能为超声空腔增强靶向给药的广泛临床应用铺平道路。这种技术的特别优点包括局部增强药物活性的能力，从而减少必要的药物剂量及其副作用，并实时监测治疗。该研究的结果有望直接转移到许多其他新型超声治疗应用中，如高强度聚焦超声（HIFU）的非侵入性组织消融、声止血和超声诱导的经颅药物输送血脑屏障打开。

High amplitude ultrasound waves propagating through tissue have been recently reported to induce a range of potentially beneficial phenomena, such as rapid tissue heating, increased permeability of cells to large drug molecules (sonoporation) or enhanced activity of drugs. These bioeffects are heavily correlated with the ultrasound-induced nucleation and subsequent excitation of micron-sized bubbles, yielding two types of acoustic cavitation activity: (1) inertial cavitation, which dramatically increases the energy transfer to tissue and can cause rapid heating and mechanical damage, and (2) stable cavitation, whereby bubbles act as micropumps that dramatically enhance the local mixing and transport length scales of drug molecules. In cancer treatment, local heating combined with chemotherpay will render cancer cells more sensitive to treatment, whilst local micropumping of the drug can help overcome delivery problems arising from the highly complex tumour structure. In the context of breaking down blood clots for stroke therapy, cavitation-enhanced mixing will promote delivery of the drug to a site of low blood flow and greatly increase the diffusion of the thombolyic drug across the clot surface.However, the nucleation of cavitating microbubbles and subsequent interaction with cells in biologically relevant media remain poorly understood. The objectives of the proposed research therefore are (i) to investigate the potential of cell- and site-specific cavitation nucleation using commercially available targeted nanoparticles currently being developed for molecular imaging; (ii) to understand and optimize the mechanism by which ultrasound and cavitation can enhance local drug delivery and drug activity across inaccessible interfaces such as tumours or blood clots; (iii) to develop clinically relevant means of monitoring cavitation activity and exploit them for real-time monitoring of drug delivery and (iv) to test the optimized drug delivery and treatment monitoring protocols in a clinically relevant organ model.It is hoped that the proposed resarch will pave the road for widespread clinical uptake of cavitaiton-enhanced targeted drug delivery by ultrasound. Particular advantages of this technique will include the ability to locally enhance drug activity, thus reducing the necessary drug dosages and their side effects, and to monitor therapy in real time. The outcomes of the proposed research are expected to be directly transferable to many other novel therapeutic ultrasound applications, such as non-invasive tissue ablation by High-Intensity Focussed Ultrasound (HIFU), acoustic haemostasis and ultrasound-induced opening of the blood-brain barrier for transcranial drug delivery.