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.

Public Health Relevance

Laboratory evaluation of therapeutic agents is essential for drug development, yet it can be fraught with challenges such as determining appropriate dose, dosing regiments, and length of treatment. To address these challenges, we propose to develop a novel and versatile implantable delivery device that can control the drug release remotely. This device can significantly impact the preclinical evaluation of therapeutic agents and regimens.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21GM111544-01
Application #
8755681
Study Section
Special Emphasis Panel (ZGM1-BBCB-A (BI))
Program Officer
Friedman, Fred K
Project Start
2014-08-15
Project End
2017-06-30
Budget Start
2014-08-15
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$199,375
Indirect Cost
$74,375
Name
Methodist Hospital Research Institute
Department
Type
DUNS #
185641052
City
Houston
State
TX
Country
United States
Zip Code
77030