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Long-distance tracing of the lymphatic system with a CT/fluorescence dual-modality nanoprobe for surveying tumor lymphatic metastasis Guoqiang Xu, Yuan Qian, Hao Zheng, Sha Qiao, Lisen Lu, Dongmei Yan, Liujuan Wu, Xiaoquan Yang, Qingming Luo, and Zhihong Zhang Bioconjugate Chem., Just Accepted Manuscript • Publication Date (Web): 19 Mar 2019 Downloaded from http://pubs.acs.org on March 19, 2019
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Bioconjugate Chemistry
Long-Distance Tracing of the Lymphatic System with a CT/Fluorescence Dual-Modality Nanoprobe for Surveying Tumor Lymphatic Metastasis Guoqiang Xu1,2#, Yuan Qian1,2#, Hao Zheng1,2, Sha Qiao1,2, Dongmei Yan1,2, Lisen Lu1,2, Liujuan Wu1,2, Xiaoquan Yang1,2, Qingming Luo1,2, Zhihong Zhang1,2* 1Britton
Chance Center for Biomedical Photonics, Wuhan National Laboratory for
Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei, 430074, China. 2MoE
Key Laboratory for Biomedical Photonics, Collaborative Innovation Center for Biomedical
Engineering, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, China. #These
authors contributed equally to this work.
*e-mail:
[email protected] Abstract Noninvasive visualization of deep tissue lymphatic metastasis is crucial for diagnosing malignant tumors and predicting prognosis. However, the limited diffusivity and specificity of imaging contrast agents that are transported in lymph vessels (LVs), even for those agents delivered by nanocarriers, make long-distance tracing of the lymphatic system in vivo challenging. Here, we develop a CT/fluorescence dual-modality phospholipid nanoprobe (PL(I/D)NP) with a negative charge and sub-60 nm size. By using micro-CT, we noninvasively traced the LVs from the subcutaneous injection site in feet to the thoracic ducts with an entire length of 68 mm and measured the volume of the lymph nodes (LNs) and their separation distance along the LVs. For diagnostic imaging of tumor lymphatic metastasis, all LNs with metastasis were identified in vivo. Thus, with their long-distance diffusivity, high lymphatic capillary specificity and quantifiability, the PL(I/D)NPs combined with noninvasive imaging accurately depicted the changes in the
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lymphatic system under pathologic conditions, especially cancer metastasis, which indicates their high potential for clinical applicability. Keywords: lymphatic system, nanoparticle, micro-CT, fluorescent imaging, lymphatic metastasis
Introduction The lymphatic system performs a crucial function in collecting circulating fluid, macromolecules and cells from tissues for return to the blood circulation through a network of vessels and nodes.1-3 The lymphatic system sensitively responds to various pathological conditions, such as lymphedema, cancer metastases, inflammation and related immune responses.4,
5
The
structural and pathophysiological changes of the lymphatic system (e.g., enlargement, lymphangiogenesis, and lymph flow increase) are considered important diagnostic indexes for serious diseases.6-8 For instance, tumor cells easily enter the hyperplastic lymph vessels (LVs) around the tumor, metastasize to its draining lymph node (LN), and even migrate to further LNs, resulting in LN swelling.9, 10 Therefore, a systemic, precise and quantitative in vivo map of the lymphatic system is crucial for the early diagnosis of serious diseases and beneficial for designing treatment plans for diseases.11-13 Because the flow of blood through vascular capillaries is much faster than the flow of lymph through lymph capillaries, small molecules (
