Novel Piezoelectric Amino-acid Ultrasound Transducer to Deliver Drugs Through the Blood Brain Barrier

摘要 由于血脑屏障的存在，神经退行性疾病和脑癌的治疗具有挑战性 (BBB)，由脑微血管内皮细胞之间的紧密连接和 阻止大多数治疗药物进入脑组织。在几种已报道的方法中， 超声(US)已被证明是促进BBB开放的最有效和最安全的方法。 然而，国外US对头盖骨较薄的小动物的疗效有限。在人类的情况下， 厚厚的头骨吸收了美国90%以上的能量，需要大量的外部美国 换能器，这通常需要几个小时的刺激，并需要乏味的磁共振监测在 超音速。此外，这种广泛的过程只对一次性刺激有用，而研究表明 BBB的开放需要美国的重复申请。植入的美国换能器因此成为一种 很好的替代方案。不幸的是，商业化的美国换能器依赖于传统的压电材料， 它们含有有毒元素，如PZT(锆钛酸铅)中的铅，因此无法降解 需要进行侵入性脑部手术才能移除。为了克服这些问题，PI的小组最近开发了 基于聚L-丙交酯(PLLA)的新型可生物降解压电换能器。然而，PLLA有一个适度的 因此不能产生强大的超声来打开脑组织深处的血脑屏障。 甘氨酸是一种可生物降解的安全氨基酸，已被发现具有极高的压电性 恒定，甚至可以与PZT这样的压电陶瓷相媲美。不幸的是，甘氨酸晶体很脆。 而且难以处理，这使得这种材料在用于高性能压电美国方面具有挑战性 换能器。在这里，我们提出了一种新的材料加工和器件制造策略，以(1)制造 一种可生物降解的、灵活的、易于使用的、由嵌入其中的甘氨酸晶体组成的高度压电的纳米纤维膜 一种聚己内酯(PCL)聚合物基质和(2)使用这种柔性甘氨酸/聚合物纳米纤维来创建 植入脑内的强大的超声换能器，有助于药物通过血脑屏障输送 (Bbb)用于治疗脑癌。我们的主要假设是；基于甘氨酸的超声换能器 将能够提供足够的声波，以促进BBB的安全和瞬时打开 通过血脑屏障传播抗癌药物以治疗脑癌。为了证明这一假设，我们设计了 该项目有三个具体目标。目标1是评估材料的压电性能，表征功能材料 寿命，并评估甘氨酸/PCL换能器的体外声场。目标2是评估安全(当地和 植入的换能器和在大型动物模型中应用的US。目标3是评估 体内植入换能器+抗癌药物治疗的抗肿瘤效果。

Abstract Neurodegenerative diseases and brain cancers are challenging to treat due to the presence of blood brain barrier (BBB), which is formed by tight junctions between endothelial cells in the microvasculature of the brain and prevents most of the therapeutics from access to the brain tissues. Among several reported approaches, ultrasound (US) has been demonstrated to be the most effective and safe method to facilitate the BBB opening. External US is however limited in efficacy to small animals whose skull bone is thin. In the case of humans, the thick skull bone absorbs more than 90% of US energy, requiring large and bulky arrays of external US transducers, which often consumes several hours of stimulation and requires tedious MRI monitoring during the sonication. Moreover, this extensive process is only useful for a single-time stimulation while research has shown the opening of BBB requires repetitive application of US. Implanted US transducers have thus emerged as an excellent alternative. Unfortunately, commercial US transducers rely on conventional piezoelectric materials, which contain toxic elements such as Lead in PZT (Lead Zirconate Titanate) and are non-degradable, therefore requiring invasive brain-surgery for removal. To overcome these problems, the PI’s group has recently developed a new biodegradable piezoelectric transducer, based on Poly-L-Lactide (PLLA). PLLA however has a modest piezoelectric constant and thus cannot generate a powerful US to open the BBB deep inside the brain tissue. Glycine, a biodegradable and safe amino acid, has been found to possess an extremely high piezoelectric constant, even comparable to that of piezoelectric ceramics like PZT. Unfortunately, glycine crystals are brittle and difficult-to-handle, rendering the material challenging to be used for high performance piezoelectric US transducer. Here, we propose a new strategy for material processing and device fabrication to (1) manufacture a biodegradable, flexible, easy-to-use, and highly piezoelectric nanofiber film of glycine crystals embedded inside a polycaprolactone (PCL) polymeric matrix and (2) employ this flexible glycine/polymer nanofibers to create a powerful US transducer which is implanted into the brain to facilitate drug-delivery through the blood-brain barrier (BBB) for the treatment of brain cancers. Our major hypothesis is that; the glycine-based ultrasound transducer will be able to provide a sufficient acoustic wave which can facilitate a safe and transient opening of BBB for the diffusion of anti-cancer drugs through the BBB to treat brain cancers. To demonstrate the hypothesis, we design the project with three specific aims. Aim 1 is to assess the piezoelectric performance, characterize the functional lifetimes, and evaluate acoustic field from the glycine/PCL transducer in vitro. Aim 2 is to asses safety (local and systemic toxicity) of the implanted transducer and the applied US in a large animal model. Aim 3 is to assess anti-tumor efficacy of the treatment using the implanted transducer + anti-cancer drugs in vivo.