Full length articleTumor-targeting CuS nanoparticles for multimodal imaging and guided photothermal therapy of lymph node metastasis
Graphical abstract
Introduction
Gastric cancer is one of the most common malignancy with the third leading cause of cancer death worldwide [1], [2]. It is found that gastric cancer has a high incidence of metastasis to lymph nodes when it is discovered, with about 85% of all gastric cancer patients diagnosed with lymph node metastasis in clinics. This makes the five-year survival rate generally less than 10% [3]. Lymph node metastasis has been recognized as one of the most important independent prognostic factors for gastric cancer patients [4]. It is vital to differentiate the metastatic lymph nodes from non-metastatic ones in patients, which can guide the following therapy to stop further metastasis of cancer cells. Until now, surgical dissection to remove both the primary gastric cancer and metastatic lymph nodes is still the only way for gastric cancer therapy in clinics. However, extended dissection of lymph nodes by surgery usually induces the postoperative risk of complications, including lymphorrhea, pancreatic fistula and abdominal abscess, leading to prolonged inflammation, increased death risk, and reduced long-term survival rate [5], [6], [7], [8], [9]. Thus, the development of new therapeutic methods enabling the accurate removal of metastatic gastric cancer cells in lymph nodes with minimum injuries to normal tissue is highly demanded.
Photothermal therapy (PTT) is an emerging noninvasive and effective therapeutic method that has attracted tremendous attentions in the past decades. PTT involves the use of near-infrared (NIR) light absorbing agents (known as photothermal agents), which can generate heat upon irradiation by an NIR laser, leading to elevated local tumor temperature that can cause irreversible tumor cell death. Compared to the traditional cancer therapies (i.e., surgery, chemotherapy, radiotherapy), PTT has advantages of being spatially and temporally controllable to achieve localized therapy, avoiding unnecessary damage to normal tissues. Moreover, recent evidences have also uncovered that PTT can also stimulate immunological effects to destroy the remaining cancer cells, preventing further metastasis [10], [11], [12], [13]. Those advantages have prompted people to investigate PTT as an alternative method to surgery for the treatment of lymph node metastasis. Many kinds of photothermal nanomaterials, including gold nanoparticles [14], [15], [16], [17], [18], [19], carbon nanotubes, graphene [20], [21], [22], transition metal oxide/sulfide nanoparticles [23], [24], [25], and organic nanoparticles [26], [27], [28], [29], [30] have been developed as PTT agents to combat cancer metastasis in lymph nodes. For instance, semiconductor copper sulfide (CuS) nanoparticles that possess strong NIR absorbance above 800 nm have shown high photothermal properties enabling both photoacoustic imaging and PTT of subcutaneous tumors as well as lymph node metastasis. Moreover, radionuclides such as 64Cu or 131I could be further doped to form radioactive CuS nanoparticles, allowing for positron emission tomography (PET) imaging and combined PTT/radiotherapy of cancers [31], [32], [33], [34], [35], [36], [37]. Despite the encouraging results, the selective entry into tumor cells, especially metastatic tumor cells in lymph nodes, and specific ablation of tumors by these CuS nanoparticles is still limited due to the lack of tumor targeting ability. In addition, they were generally non-fluorescent, which limited their wide applications for rapid and real-time fluorescence imaging and mapping of lymph node metastasis [38], [24], [39], [40], [41], [42].
Herein, we develop a fluorescent CuS nanoparticle (denoted as RGD-CuS-Cy5.5) integrating a tumor targeting ligand cRGD [43], [44], [45], [46], [47] and an NIR organic dye Cy5.5 for combined fluorescence/CT dual modality imaging and selective PTT of gastric cancer metastasis in sentinel lymph nodes (SLN). We show that RGD-CuS-Cy5.5 can readily drain into SLN and selectively enter into MNK45 gastric tumor cells via αvβ3 receptor-mediated endocytosis, offering strong NIR fluorescence at 695 nm and remarkable CT contrast indicative of SLN metastasis. Guided by the imaging, localized PTT of SLN metastasis in gastric tumors bearing mice is then performed to induce efficient tumor cell death, resulting in complete removal of tumors in SLN without obvious toxicity. This study demonstrates the application of gastric cancer targeting CuS nanoparticles for both multimodality mapping and therapy of lymph node metastasis, which may provide an alternative method for the treatment of gastric cancer lymph node metastasis amenable for clinical applications.
Section snippets
General materials and methods
All chemicals and biological reagents were purchased from commercial suppliers and used without further purification. CuCl2·2H2O and thioacetamide were purchased from Aladdin Reagent Corporation (Shanghai, China). SH-PEG2000-COOH was purchased from JenKem Technology Co., Ltd. NH2-cRGD was purchased from GL Biochem Ltd (Shanghai, China). Calcein AM, propidium iodide (PI), Lyso-Tracker Green, and Hoechst 33,342 were obtained from KeyGen Biotech. Co. Ltd. (Nanjing, China).
The fluorescence spectra
Design of fluorescent tumor targeting CuS nanoparticles
Fig. 1a showed the design of tumor targeting CuS nanoparticles (RGD-CuS-Cy5.5), consisting of a polyethylene glycol (PEG2000) functionalized CuS nanoparticle, a tumor targeting ligand cRGD and an NIR fluorophore Cy5.5. CuS nanoparticles were chosen as the PTT agents because of the small size, low systemic toxicity and high photothermal properties at NIR region [33], [34]. Moreover, CuS nanoparticles could also be used as efficient CT imaging contrast agents due to the strong ability to absorb
Conclusions
In conclusion, we have reported the development of fluorescent RGD-CuS-Cy5.5 nanoparticles for multimodal fluorescence/CT imaging and targeting PTT of SLN metastasis of gastric tumor cells in living mice. We have demonstrated that RGD-CuS-Cy5.5 possessed strong NIR absorbance as well as high NIR fluorescence and X-ray attenuate property, offering a remarkable photothermal property for effective PTT and bimodal fluorescence/CT signals for in vivo mapping of SLN metastasis. Moreover, the covalent
Acknowledgements
We would like to acknowledge Prof. Yin Ding for her help with MRI acquirement. Financial supports from the National Natural Science Foundation of China (81671751, 81371516, 81501441, 81601463, 21632008, 21775071), Foundation of National Health and Family Planning Commission of China (W201306), Social Development Foundation of Jiangsu Province (BE2015605), the Natural Science Foundation of Jiangsu Province (BK20150109, BK20150567, BK20171118), Jiangsu Province Health and Family Planning
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