High frequency acoustic permeabilisation of drugs through tissue for localised mucosal delivery
High frequency acoustic permeabilisation of drugs through tissue for localised mucosal delivery
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DOI：
10.1039/c8lc00355f
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发表时间：
2018-11-07
期刊：
影响因子：
6.1
通讯作者：
Yeo, Leslie Y.
中科院分区：
文献类型：
--
作者：
Ramesan, Shwathy;Rezk, Amgad R.;Yeo, Leslie Y.
大多数传染病是通过眼、鼻、口、阴道和直肠表面的粘膜进入人体的。由于感染可以通过激发粘膜免疫细胞丰富区域的局部免疫反应来有效预防，因此直接靶向将疫苗递送到这些表面是疫苗给药的有效途径。然而，提供足够的驱动力来穿透粘膜表面的黏液衬里和上皮屏障是具有挑战性的，这些屏障旨在有效地阻止异物进入，但不能过度，以至于治疗剂深入血管化的粘膜下区域，在那里它们主要被体循环吸收，从而导致免疫反应弱得多。在这项工作中，我们证明了利用高频声学在猪颊模型粘膜中可控地定位和最大化小分子和大分子模型治疗剂的可能性。与低（kHz阶）频率的体超声不同，这些高频（bbb10 MHz）表面波不会产生空化，而空化会导致大分子穿透深度超过100 m阶厚的粘膜层，并且已知会导致相当大的细胞/组织损伤并因此形成疤痕。通过声照射频率、功率和暴露时间等系统参数，我们发现可以调整穿透深度，使95%以上的药物被定位在粘膜层内，同时保持其结构完整性。
The majority of infectious diseases enter the body through mucosal membranes that line the ocular, nasal, oral, vaginal and rectal surfaces. As infections can be effectively prevented by instigating a local immune response in the immunocyte-rich regions of the mucosa, an efficacious route of vaccine administration is to directly target their delivery to these surfaces. It is nevertheless challenging to provide sufficient driving force to penetrate both the mucus lining as well as the epithelial barrier of the mucosal surfaces, which are designed to effectively keep foreign entities out, but not excessively such that the therapeutic agent penetrates deeper into the vascularised submucosal regions where they are mostly taken up by the systemic circulation, thus resulting in a far weaker immune response. In this work, we demonstrate the possibility of controllably localising and hence maximising the delivery of both small and large molecule model therapeutic agents in the mucosa of a porcine buccal model using high frequency acoustics. Unlike their low (kHz order) frequency bulk ultrasonic counterpart, these high frequency (>10 MHz) surface waves do not generate cavitation, which leads to large molecular penetration depths beyond the 100 m order thick mucosal layer, and which has been known to cause considerable cellular/tissue damage and hence scarring. Through system parameters such as the acoustic irradiation frequency, power and exposure duration, we show that it is possible to tune the penetration depth such that over 95% of the delivered drug are localised within the mucosal layer, whilst preserving their structural integrity.