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，必须在小动物模型中对新型治疗药物进行体内评价。由于不适当或次优的给药方案、给药或治疗持续时间等，很大一部分实验治疗在此阶段失败。确定最有效和毒性最小的给药策略是昂贵和耗时的药物递送的常规手段，即注射和口服灌胃。用于体内测试的其他递送技术，如渗透泵和聚合物植入物，不能调节或打开和关闭，并且在聚合物制剂的情况下，可能与释放爆发和释放低谷相关，这可能进一步使药剂的体内评价复杂化。其他技术，如微芯片，体积大，不适合小动物研究。我们的研究小组专注于开发可植入的，基于纳米通道的设备，用于控制和长期药物输送：纳米通道输送系统或NDS。nDS基于具有限定数量的密集堆积的纳米通道的硅膜，所述纳米通道具有对通道尺寸和几何形状的严格公差。在这个应用中，我们建议开发一种多功能和远程控制的药物输送仪器，通过利用物理和静电门控进行体内实验室分析 在外加低功率电场下，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）通过用铂电极涂覆纳米通道膜来设计和组装远程控制的纳米通道递送植入物。将在体外研究其电极的电化学降解。我们将开发和测试电子电路和射频（RF）通信。我们将组装植入物，包括电池，电子器件，药物储存器和膜。目的2）对植入剂进行表征，并考察三种不同药物的可调和远程控制释放。在体外测试RF控制药物释放之前，将通过表征与遥控器的通信和系统稳健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Sprague-Dawley大鼠体内的药代动力学来研究射频控制的植入物，作为植入物将按设计工作的概念验证。将组装、装载射频控制植入物，并将其皮下植入大鼠背部。释放将在8周内远程控制，我们将分析血液样品中通过LC-MS测量的药物浓度。将收获植入物周围的组织，并通过组织病理学评估纤维化和炎症。如果成功，我们的建议将提供一种新的，自动的，多功能的，并有可能通用的，基于纳米通道的仪器，用于在体内分析的实验药物和给药方案的广泛范围。该装置可以显著影响治疗剂的体内测试的时间、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.