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Novel nanotechnology-based optical stimulation platform for predictive cardiotoxicity assessment

Award Number: R43TR001911
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT The estimated average industry cost per new prescription drug approval currently now exceeds $2.5 billion. One of the critical factors contributing to the rising costs of drug development is a non-optimal focus of pre- clinical studies for detecting potential cardiac liabilities of novel drug candidates. Recognizing this fact, the biomedical community has recently proposed a new paradigm for cardiac safety studies: the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative. It includes a shift from over-simplified hERG-focused cardiotoxicity screening to evaluation of drug effects on multiple ion channels contributing to action potential in human stem cell-derived cardiomyocytes (CMs). Optical cell-based drug screening assays that monitor the dynamics of intracellular calcium concentrations and the cell membrane potential in stem cell-derived CMs are well-suited for detecting drug candidates with cardiac liabilities. Since drug-induced effects are often dependent on the activation state of cells, it is crucial to be able to stimulate CMs during drug screening. We propose to address this need by offering a revolutionary nanotechnology-based platform for non-invasive optical stimulation of CMs. We designed this optoelectronic platform by taking advantage of the unique properties of graphene, a “wonder material of the 21th century”. These properties ensure excellent biocompatibility of graphene-coated substrates, the ability to efficiently convert light into electricity, and compatibility with optical detection methods. Our preliminary results demonstrate that light can induce fast and reversible changes in contractile and electrical activity of stem cell-derived CMs cultured on graphene-coated substrates. Furthermore, we confirmed that optical stimulation via G-coated substrates can enable all-optical evaluation of use-dependent drug effects on the CM activity. To streamline the customer adoption of our graphene-based optical stimulation platform and incorporation it in into optical drug-screening assays, we are proposing to perform the following activities: a) developing a procedure for graphene deposition into cell culture multi-well plates, following by manufacturing of high-quality graphene-coated plates; b) optimizing the various parameters of voltage and calcium all-optical assays (including a dual-light stimulation protocol) on a customized microscopy system; c) transferring optimized all-optical assays to well-regarded high-through and high-content imaging instruments and performing screening of multiple benchmark compounds on optically stimulated CMs. We expect that optical stimulation of CMs via graphene- based substrates will dramatically increase the predictive value of cardiotoxicity screening assays. The proposed all-optical assays will be instrumental in correctly detecting genuine pro-arrhythmia risks early in the drug discovery process, thus reducing the spending and drug development time.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2017	NANOTOOLS BIOSCIENCE	309 HESTIA WAY	ENCINITAS	CA	92024	SAN DIEGO	USA	Research Infrastructure Programs	000	1	2/21/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2017	NANOTOOLS BIOSCIENCE	309 HESTIA WAY	ENCINITAS	CA	92024	SAN DIEGO	USA	Research Infrastructure Programs	000	1	7/9/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2017	NANOTOOLS BIOSCIENCE	309 HESTIA WAY	ENCINITAS	CA	92024	SAN DIEGO	USA	Research Infrastructure Programs	000	1	8/15/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $325,000 )
2017	2017	NANOTOOLS BIOSCIENCE	309 HESTIA WAY	ENCINITAS	CA	92024	SAN DIEGO	USA	Research Infrastructure Programs	000	1	8/23/2017	NEW	$325,000
														Subtotal = $325,000

Grand Total All Awards = $325,000

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Novel nanotechnology-based optical stimulation platform for predictive cardiotoxicity assessment

Award Number: R43TR001911

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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