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Drug Discovery Using Bioluminescence Imaging

Feb 24, 2022 11:00:00 AM / by Champions Oncology

Blue Explosion

Molecular imaging techniques have become an essential tool in drug discovery because they provide critical insights into drug penetration and efficacy using non-invasive approaches. Several different molecular imaging methods exist, including ultrasound, radionuclide imaging, magnetic resonance, and optical imaging[1]. Optical imaging has grown in popularity because it is based on bioluminescence or fluorescence imaging techniques. Bioluminescence imaging (BLI) is well suited to drug discovery in animal models and in vitro systems because it does not require any radioactive reagents, has high molecular sensitivity with low background, and reagents are widely available and not especially costly. Here we highlight key features of BLI that makes this method a drug discovery essential.

 

1. Clear Imaging: BLI methods first emerged as strategies to study living cells in mouse models and has been instrumental in tracking multiple immune cell subsets concurrently under homeostatic conditions or in disease states such as cancer[2]. These studies can track the fates and functions of T cells or B cells that have been engineered to express enzymes such as luciferase. Different types of luciferase enzymes have been found in terrestrial and marine organisms but are not expressed in mammals. Mice engineered to express luciferase are treated with luciferase substrates, which causes a bioluminescent reaction that generates light at wavelengths specific to each luciferase type. This light is detected in specialized light-excluding apparatuses and imaged in real time for up to 60 min. Thus, BLI methods are highly sensitive and associated almost no background noise, which allows for the detection of light emitted in deep tissues as well as tumors[3].

 

2. High-throughput screens: BLI can be used in high-throughput screens (HTS) of targeted therapies for different tumor types. Cancer cell lines can be transfected with luciferase as a reporter gene linked to different aberrant target genes associated with a specific tumor such as kinases, proteases, apoptosis proteins, or transcription factors. This modified cancer cell line can be screened with a library of drug compounds in an HTS format to identify potential anti-tumor responses[4]. These luciferase-expressing cancer cell lines can also be implanted into mice for evaluation of leading drug candidates in vivo. In addition, HTS screens can be used to evaluate toxicity of drug candidates.

 

3. Better Models: The noninvasive nature of BLI makes it well suited to studying certain aspects of tumors, including changes in volume of primary tumors and the spread of tumor cells to secondary sites. Mice with luciferase-expressing tumors can be injected multiple times and by different routes with luciferin substrate, which is valuable for longitudinal studies of tumor growth and metastasis or for monitoring drug efficacy over time[5]. Typically, cancer cell lines have most commonly be used for luciferase transfection, but advances in lentivirus-based transduction enabled patient derived xenografts (PDX) to be modified to express luciferase. This advance has allowed for better preclinical evaluation of drug candidates for solid tumors and hematologic malignancies[6],[7].

Applications of Bioluminescence

BLI is not a perfect method as it does require genetic manipulation of cells of interest and is not ideal for detailed anatomical imaging. This method is outstanding for preclinical drug screening and characterization of basic tumor characteristics. As an affordable and accessible method, BLI remains a workhorse for many investigators.

 

Preclinical In Vivo Imaging in Systemic Tumor Models - download now

 


[1] Chen Z-Y, Wang Y-X, Lin Y, Zhang J-S, Yang F, Zhou Q-L, Liao Y-Y. “Advance of Molecular Imaging Technology and Targeted Imaging Agent in Imaging and Therapy”, BioMed Research International, vol. 2014, Article ID 819324, 12 pages, 2014. https://doi.org/10.1155/2014/819324.

[2] Dubey P. Visualization of Immune Cell Reconstitution by Bioluminescent Imaging. Methods Mol Biol. 2018;1790:127-136.

[3] Contag CH, Jenkins D, Contag PR, Negrin RS. Use of reporter genes for optical measurements of neoplastic disease in vivo. Neoplasia. 2000 Jan-Apr;2(1-2):41-52.

[4] Fan F, Wood KV. Bioluminescent assays for high-throughput screening. Assay Drug Dev Technol. 2007 Feb;5(1):127-36.

[5] Khalil AA, Jameson MJ, Broaddus WC, Chung TD, Golding SE, Dever SM, Rosenberg E, Valerie K. Subcutaneous administration of D-luciferin is an effective alternative to intraperitoneal injection in bioluminescence imaging of xenograft tumors in nude mice. ISRN Mol Imaging. 2013;2013:689279.

[6] Contreras-Zárate MJ, Ormond DR, Gillen AE, Hanna C, Day NL, Serkova NJ, Jacobsen BM, Edgerton SM, Thor AD, Borges VF, Lillehei KO, Graner MW, Kabos P, Cittelly DM. Development of Novel Patient-Derived Xenografts from Breast Cancer Brain Metastases. Front Oncol. 2017 Nov 2;7:252..

[7] Jones L, Richmond J, Evans K, Carol H, Jing D, Kurmasheva RT, Billups CA, Houghton PJ, Smith MA, Lock RB. Bioluminescence Imaging Enhances Analysis of Drug Responses in a Patient-Derived Xenograft Model of Pediatric ALL. Clin. Cancer Res. 2017 Jul 15;23(14):3744-3755.

 

Tags: Preclinical In Vivo Imaging