Imaging epileptic foci in mouse models via a low-density lipoprotein receptor-related protein-1 targeting strategy
Cong Wang,
Jianping Zhang,
Shaoli Song,
Zhi Li,
Shujie Yin,
Wenjia Duan,
Zixuan Wei,
Ming Qi,
Wanbing Sun,
Lu Zhang,
Luo Chen,
Xihui Gao,
Ying Mao,
Hao Wang,
Liang Chen,
Cong Li
Affiliations
Cong Wang
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China; National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Shanghai, China
Jianping Zhang
Institute of Modern Physics, Fudan University, Shanghai, China; Shanghai Engineering Research Center for Molecular Imaging Probes, Shanghai, China; Department of Nuclear Medicine, Shanghai Cancer Center, Fudan University, Shanghai, China; Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan University, Shanghai, China
Shaoli Song
Department of Nuclear Medicine, Shanghai Cancer Center, Fudan University, Shanghai, China
Zhi Li
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
Shujie Yin
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
Wenjia Duan
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
Zixuan Wei
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
Ming Qi
Department of Nuclear Medicine, Shanghai Cancer Center, Fudan University, Shanghai, China
Wanbing Sun
Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China
Lu Zhang
Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
Luo Chen
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
Xihui Gao
School of Basic Medical Sciences, Fudan University, Shanghai, China
Ying Mao
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
Hao Wang
National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Shanghai, China; Corresponding author.
Liang Chen
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China; Corresponding author.
Cong Li
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China; Corresponding author.
Background: In the setting of drug-resistant epilepsy (DRE), the success of surgery depends on the ability to accurately locate the epileptic foci to be resected or disconnected. However, the epileptic foci in a considerable percentage of the DRE patients cannot be adequately localised. This warrants the need for a reliable imaging strategy to identify the “concealed” epileptic regions. Methods: Brain specimens from DRE patients and kainate-induced epileptic mouse models were immuno-stained to evaluate the integrity of the blood-brain barrier (BBB). The expression of low-density lipoprotein receptor-related protein-1 (LRP1) in the epileptic region of DRE patients and kainate models was studied by immunofluorescence. A micellar-based LRP1-targeted paramagnetic probe (Gd3+-LP) was developed and its ability to define the epileptic foci was investigated by magnetic resonance imaging (MRI). Findings: The integrity of the BBB in the epileptic region of DRE patients and kainate mouse models were demonstrated. LRP1 expression levels in the epileptic foci of DRE patients and kainate models were 1.70–2.38 and 2.32–3.97 folds higher than in the control brain tissues, respectively. In vivo MRI demonstrated that Gd3+-LP offered 1.68 times higher (P < 0.05) T1-weighted intensity enhancement in the ipsilateral hippocampus of chronic kainite models than the control probe without LRP1 specificity. Interpretation: The expression of LRP1 is up-regulated in vascular endothelium, activated glia in both DRE patients and kainate models. LRP1-targeted imaging strategy may provide an alternative strategy to define the “concealed” epileptic foci by overcoming the intact BBB. Funding: This work was supported by the National Natural Science Foundation, Shanghai Science and Technology Committee, Shanghai Municipal Science and Technology, Shanghai Municipal Health and Family Planning Commission and the National Postdoctoral Program for Innovative Talents.
