A tunable delivery platform for in vivo investigation of therapeutics

描述(由申请人提供)：在临床试验之前，在小动物模型中对新的治疗药物进行活体评估是必不可少的。在这一阶段，很大一部分实验疗法由于不适当或不理想的给药方案、剂量或治疗持续时间等原因而失败。确定最有效和毒性最小的给药策略是昂贵和耗时的，通过传统的药物输送手段，即注射和口服。用于体内试验的其他给药技术，如渗透泵和聚合物植入物，不能调谐或开启和关闭，如果是聚合物配方，可能会与释放突发和低谷相关，这可能会使试剂的体内评估进一步复杂化。其他技术，如微芯片，体积很大，不适合用于小动物研究。我们的研究小组专注于开发可植入的、基于纳米通道的装置，用于受控和长期的药物输送：纳米通道输送系统或NDS。NDS是基于硅膜，具有一定数量的密集填充的纳米通道，对通道大小和几何形状有严格的公差。在这一应用中，我们建议开发一种多功能的远程控制的药物输送仪器，通过利用物理和静电门控来进行活体实验室分析 在一个外加的低功率电场下，分子通过纳米通道。为了开发这种装置，我们提出了以下实验目标：目的1)通过在纳米通道膜上涂覆铂电极来设计和组装一种可遥控的纳米通道植入物。它们对电极的电化学降解将在体外进行研究。我们将开发和测试电子电路和射频通信。我们将组装植入物，包括电池、电子设备、药库和薄膜。目的2)对植入物进行表征，考察三种不同药物的体外可调控性。在体外测试射频控制的药物释放之前，将通过表征与遥控器的通信和系统的健壮性来检查组装的植入物。目的3)通过研究单一模型药物在健康SD大鼠体内的药代动力学，研究射频控制植入物的体内药代动力学，为植入物的设计提供理论依据。射频控制的植入物将被组装、加载并植入大鼠背部的皮下。释放将在8周内远程控制，我们将用LC-MS分析血液样本中的药物浓度。植入物周围的组织将被收获，纤维化和炎症将通过组织病理学进行评估。如果成功，我们的提议将提供一种新颖的、自动的、通用的、基于纳米通道的仪器，用于对广泛的实验药物和给药方案进行体内分析。这种设备可以显著影响治疗药物的体内测试的时间、成本和成功。

DESCRIPTION (provided by applicant): In vivo evaluation of novel therapeutic agents in small animal models is essential prior to clinical trials. A significant portion of experimental therapeutics fails during this phase due to inappropriate or suboptimal administration regimens, dosing, or duration of treatment, among others. Determining the most-effective and least-toxic administration strategy is costly and time-consuming by conventional means of drug delivery i.e. injections and oral gavage. Other delivery technologies for in vivo testing, such as osmotic pumps and polymeric implants, cannot be tuned or turned on and off, and in case of polymeric formulations, can be associated with release bursts and troughs that can further complicate in vivo evaluation of agents. Other technologies, such as Micro-chips, possess large volumes making them unsuitable for small animal studies. Our research group has focused on the development of implantable, nanochannel-based devices for controlled and long-term drug delivery: nanochannel Delivery Systems or nDS. nDS is based on a silicon membrane with a defined number of densely packed nanochannels with strict tolerances on channel size and geometry. In this application, we propose to develop a versatile and remotely controlled drug delivery instrument for in vivo laboratory analysis by leveraging physical and electrostatic gating of molecules through nanochannel under an applied low-power electrical field. To develop this device, we propose the following experimental aims: Aim 1) To design and assemble a remotely controlled nanochannel delivery implant by coating the nanochannel membranes with platinum electrodes. Their electrochemical degradation of the electrodes will be investigated in vitro. We will develop and test the electronic circuit and radio frequency (RF) -communications. We will assemble the implant, including battery, electronics, drug reservoir, and membranes. Aim 2) To characterize the implant and to investigate the tunable and remotely controlled release of three different drugs in vitro. Prior to testing RF-controlled drug release in vitro, the assembled implat will be examined by characterizing the communication with the remote controller and the system robustness. Aim 3) To study the RF-controlled implant in vivo by investigating the pharmacokinetics of a single model drug in healthy Sprague-Dawley rats as a proof-of-concept that the implant will work as designed. RF-controlled implants will be assembled, loaded, and subcutaneously implanted in the rat dorsum. The release will be remotely controlled over 8 weeks and we will analyze blood samples for the drug concentration measured by LC-MS. Tissues surrounding the implant will be harvested and fibrosis and inflammation will be assessed by histopathology. If successful, our proposal will provide a novel, automatic, versatile, and potentially universal, nanochannel-based instrument for the in vivo analysis of a broad spectrum of experimental drugs and dosing regimens. This device can significantly impact the time, cost, and success of in vivo testing of therapeutic agents.