Drug Absorption, Distribution, Metabolism and Excretion

Comparative strategies for stem cell biodistribution in a preclinical study

Authors: Fang Wang1,2, Zhe Wang1,3, Fen Wang4, Kelly Dong1,2, Jing Zhang1,3, Yun-juan Sun2, Chun-feng Liu4,5, Mei-jie Xing2, Xue Cheng2, Su Wei2, Jia-wei Zheng6, Xiong-fei Zhao6, Xiao-ming Wang6, Jie Fu1,3, Hai-feng Song1,3
1 New Drug Evaluation Platform, National Engineering Research Center for Protein Drugs, Beijing 102206, China
2 Immunoassay Department, United-Power Pharma Tech Co, Beijing 102206, China
3 Key Laboratory of Proteomics, Beijing Institute of Lifeomics, Beijing 102206, China
4 Institute of Neuroscience, Soochow University, Suzhou 215123, China
5 Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
6 Shanghai Angecon Biotechnology Co., Ltd, Shanghai 201318, China
Correspondence to: Jie Fu: 13311161618@163.com, Hai-feng Song: songhf6811@163.com,
DOI: 10.1038/s41401-019-0313-x
Received: 10 May 2019
Accepted: 30 September 2019
Advance online: 8 November 2019

Abstract

Stem cell therapy represents the potential alternative effective strategy for some diseases that lack effective treatment currently. Correspondingly, it is crucial to establish high-sensitive and reliable quantification assay for tracing exogenous cell migration. In the present study, we first used both bioluminescence imaging (BLI) indirect labeling (human norepinephrine transporter-luciferase reporter system) and 89zirconium (89Zr)-hNSCs direct labeling combined with positron emission tomography/computer tomography (PET/CT) system for tracking human neural stem cells (hNSCs) migration into the brain via nasal administration in preclinical study. But the above two methods failed to give the biodistribution profile due to their low sensitivity. Considering its superior sensitivity and absolute quantitation capability, we developed and validated the droplet digital PCR (ddPCR) targeting species-specific gene in frozen and paraffin sections, slices, and whole blood with the sensitivity of 100–200 hNSCs. Accurate and high throughput quantification could be performed using ddPCR with the coefficient of variation (CVs) of lower quality control (LQC) below 30%. In combination with immunohistochemistry and ddPCR, we confirmed the migration of hNSCs into the brain via nasal administration, which supported the efficacy of hNSCs in MPTP-treated mice, an animal model of Parkinson’s disease. In conclusion, the present study is the first to report the application of ddPCR in the pharmacokinetics profile description of tracking of hNSCs in preclinical studies.
Keywords: neural stem cells; biodistribution; bioluminescence imaging; 89Zr-PET/CT; droplet digital PCR; pharmacokinetics; MPTP mice; Parkinson disease

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