A tunable delivery platform for in vivo investigation of therapeutics

用于体内治疗研究的可调递送平台

基本信息

批准号：
9131804
负责人：
Alessandro Grattoni
金额：
$ 19.94万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9131804
关键词：
Address Adopted Animal Model Animals Back Blood specimen Clinic Clinical Trials Communication Complex Deposition Development Device Designs Devices Dose Drug Controls Drug Delivery Systems Drug Formulations Drug Kinetics Electrodes Electronics Electrostatics Equilibrium Essential Drugs Evaluation Fibrosis Formulation Geometry Harvest Health Histopathology Implant In Vitro Inflammation Injection of therapeutic agent Investigation Investigational Therapies Laboratories Length Measures Membrane Modeling Oral Pharmaceutical Preparations Phase Pump Rattus Regimen Reproducibility Research Research Personnel Resources Signal Transduction Silicon Sprague-Dawley Rats Structure System Technology Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Validation Work base controlled release cost design drug development electrical potential flexibility implant coating implantable device in vivo instrument nanochannel novel novel therapeutics platinum electrode preclinical evaluation radio frequency response success tool treatment duration

项目摘要

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.

描述（由申请人提供）：在临床试验之前，在小动物模型中对新型治疗剂进行体内评估至关重要。由于不适当或次优的给药方案、剂量或治疗持续时间等原因，很大一部分实验疗法在此阶段失败。通过传统的药物输送方式（即注射和口服灌胃）确定最有效和毒性最小的给药策略既昂贵又耗时。用于体内测试的其他递送技术，例如渗透泵和聚合物植入物，无法调节或打开和关闭，并且在聚合物制剂的情况下，可能与释放爆发和波谷相关，这可能使药物的体内评估进一步复杂化。其他技术，例如微芯片，体积庞大，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，用于受控和长期药物输送：纳米通道输送系统或 nDS。 nDS 基于硅膜，具有一定数量的密集纳米通道，对通道尺寸和几何形状具有严格的公差。在此应用中，我们建议通过利用物理和静电门控来开发一种用于体内实验室分析的多功能远程控制药物输送仪器在施加的低功率电场下分子通过纳米通道。为了开发该设备，我们提出以下实验目标：目标 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。将在体外研究它们的电极电化学降解。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。目标 2) 表征植入物并研究三种不同药物体外可调和远程控制的释放。在体外测试射频控制药物释放之前，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。目标 3) 通过研究单一模型药物在健康 Sprague-Dawley 大鼠中的药代动力学来研究体内射频控制植入物，作为植入物将按设计发挥作用的概念验证。射频控制的植入物将被组装、装载并皮下植入大鼠背部。释放将在 8 周内进行远程控制，我们将分析血液样本，通过 LC-MS 测量药物浓度。将收集植入物周围的组织，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颖的、自动的、多功能的、潜在通用的、基于纳米通道的仪器，用于广泛的实验药物和给药方案的体内分析。该设备可以显着影响治疗剂体内测试的时间、成本和成功率。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Unexpected behaviors in molecular transport through size-controlled nanochannels down to the ultra-nanoscale.

通过尺寸控制的纳米通道直至超纳米尺度的分子传输的意外行为。

DOI：
发表时间：
2018
期刊：
影响因子：
16.6
作者：
Bruno, Giacomo;Di Trani, Nicola;Hood, R Lyle;Zabre, Erika;Filgueira, Carly Sue;Canavese, Giancarlo;Jain, Priya;Smith, Zachary;Demarchi, Danilo;Hosali, Sharath;Pimpinelli, Alberto;Ferrari, Mauro;Grattoni, Alessandro
通讯作者：
Grattoni, Alessandro

Sustained Administration of Hormones Exploiting Nanoconfined Diffusion through Nanochannel Membranes.

利用纳米通道膜的纳米限制扩散来持续施用激素。

DOI：
发表时间：
2015-08
期刊：
影响因子：
0
作者：
Geninatti, Thomas;Hood, R Lyle;Bruno, Giacomo;Jain, Priya;Nicolov, Eugenia;Ziemys, Arturas;Grattoni, Alessandro
通讯作者：
Grattoni, Alessandro

The active modulation of drug release by an ionic field effect transistor for an ultra-low power implantable nanofluidic system.

用于超低功率可植入纳米流体系统的离子场效应晶体管对药物释放的主动调节。

DOI：
发表时间：
2016-11-10
期刊：
影响因子：
6.7
作者：
Bruno, Giacomo;Canavese, Giancarlo;Liu, Xuewu;Filgueira, Carly S;Sacco, Adriano;Demarchi, Danilo;Ferrari, Mauro;Grattoni, Alessandro
通讯作者：
Grattoni, Alessandro

Impedance characterization, degradation, and in vitro biocompatibility for platinum electrodes on BioMEMS.

BioMEMS 上铂电极的阻抗表征、降解和体外生物相容性。

DOI：
发表时间：
2015-02
期刊：
影响因子：
2.8
作者：
Geninatti, Thomas;Bruno, Giacomo;Barile, Bernardo;Hood, R Lyle;Farina, Marco;Schmulen, Jeffrey;Canavese, Giancarlo;Grattoni, Alessandro
通讯作者：
Grattoni, Alessandro

Leveraging electrokinetics for the active control of dendritic fullerene-1 release across a nanochannel membrane.

利用电动学主动控制树枝状富勒烯-1 在纳米通道膜上的释放。

DOI：
10.1039/c4nr06209d
发表时间：
2015-03-12
期刊：
Nanoscale
影响因子：
6.7
作者：
Bruno G;Geninatti T;Hood RL;Fine D;Scorrano G;Schmulen J;Hosali S;Ferrari M;Grattoni A
通讯作者：
Grattoni A