Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Suono Bio, Inc. 700 Main St., North, Cambridge, MA 02139, United States.
The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Department of Materials, University of Oxford, 16 Parks Road, Oxford OX1 3PH, UK.
J Control Release. 2017 Dec 28;268:113-119. doi: 10.1016/j.jconrel.2017.10.023. Epub 2017 Oct 16.
Ultrasound-mediated drug delivery in the gastrointestinal (GI) tract is a bourgeoning area of study. Localized, low-frequency ultrasound has recently been shown to enable significant enhancement in delivery of a broad set of active pharmaceutical ingredients including small molecules, proteins, and nucleic acids without any formulation or encapsulation of the therapeutic. Traditional chemical formulations are typically required to protect, stabilize, and enable the successful delivery of a given therapeutic. The use of ultrasound, however, may make delivery insensitive to the chemical formulation. This might open the door to chemical formulations being developed to address other properties besides the deliverability of a therapeutic. Instead, chemical formulations could potentially be developed to achieve novel pharmacokinetics, without consideration of that particular formulation's ability to penetrate the mucus barrier passively. Here we investigated the effect of permeant size, charge, and the presence of chemical penetration enhancers on delivery to GI tissue using ultrasound. Short ultrasound treatments enabled delivery of large permeants, including microparticles, deep into colonic tissue ex vivo. Delivery was relatively independent of size and charge but did depend on conformation, with regular, spherical particles being delivered to a greater extent than long-chain polymers. The subsequent residence time of model permeants in tissue after ultrasound-mediated delivery was found to depend on size, with large microparticles demonstrating negligible clearance from the local tissue 24h after delivery ex vivo. The dependence of clearance time on permeant size was further confirmed in vivo in mice using fluorescently labeled 3kDa and 70kDa dextran. The use of low-frequency ultrasound in the GI tract represents a novel tool for the delivery of a wide-range of therapeutics independent of formulation, potentially allowing for the tailoring of formulations to impart novel pharmacokinetic profiles once delivered into tissue.
胃肠道（GI）中超声介导的药物输送是一个新兴的研究领域。最近的研究表明，局部低频超声能够显著增强多种活性药物成分（包括小分子、蛋白质和核酸）的输送，而无需对治疗药物进行任何制剂或封装。传统的化学制剂通常需要用于保护、稳定和实现特定治疗药物的成功输送。然而，超声的使用可能使输送对化学制剂不敏感。这可能为开发旨在解决治疗药物输送以外的其他特性的化学制剂开辟了道路。相反，化学制剂有可能被开发为实现新型药代动力学，而无需考虑该特定制剂被动穿透黏液屏障的能力。在这里，我们研究了使用超声时渗透物大小、电荷和化学渗透增强剂的存在对 GI 组织输送的影响。短暂的超声处理能够将包括微粒在内的大渗透物输送到结肠组织深处。输送相对独立于大小和电荷，但确实取决于构象，具有规则、球形的颗粒比长链聚合物输送得更多。在体外超声介导输送后，模型渗透物在组织中的随后停留时间被发现取决于大小，大微粒在输送后 24 小时从局部组织中几乎没有清除。在体内使用荧光标记的 3kDa 和 70kDa 葡聚糖进一步证实了清除时间对渗透物大小的依赖性。在胃肠道中使用低频超声代表了一种新的工具，可用于输送广泛的治疗药物，而无需考虑制剂，这可能允许根据输送到组织后的新型药代动力学特征来定制制剂。
