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Dual targeting luminescent gold nanoclusters for tumor imaging and deep tissue therapy

作者： Dan Chen^a, Bowen Li^b, Songhua Cai^c, Peng Wang^c, Shuwen Peng^a, Yuanzhi Sheng^a, Yuanyuan He^a, Yueqing Gu^a , Haiyan Chen^a

^a Department of Biomedical Engineering, School of Engineering, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Lane, Gulou District, Nanjing 210009, China

^b Department of Bioengineering, University of Washington, Seattle, USA

^c Nanjing University Sub-Atomic Resolution Electron Microscopy Laboratory, College of Engineering and Applied Sciences, Nanjing University, China

摘要：Dual targeting towards both extracellular and intracellular receptors specific to tumor is a significant approach for cancer diagnosis and therapy. In the present study, a novel nano-platform (AuNC-cRGD-Apt) with dual targeting function was initially established by conjugating gold nanocluster (AuNC) with cyclic RGD (cRGD) that is specific to αvβ3integrins over-expressed on the surface of tumor tissues and aptamer AS1411 (Apt) that is of high affinity to nucleolin over-expressed in the cytoplasm and nucleus of tumor cells. Then, AuNC-cRGD-Apt was further functionalized with near infrared (NIR) fluorescence dye (MPA), giving a NIR fluorescent dual-targeting probe AuNC-MPA-cRGD-Apt. AuNC-MPA-cRGD-Apt displays low cytotoxicity and favorable tumor-targeting capability at both in vitro and in vivo level, suggesting its clinical potential for tumor imaging. Additionally, Doxorubicin (DOX), a widely used clinical chemotherapeutic drug that kill cancer cells by intercalating DNA in cellular nucleus, was immobilized onto AuNC-cRGD-Apt forming a pro-drug, AuNC-DOX-cRGD-Apt. The enhanced tumor affinity, deep tumor penetration and improved anti-tumor activity of this pro-drug were demonstrated in different tumor cell lines, tumor spheroid and tumor-bearing mouse models. Results in this study suggest not only the prospect of non-toxic AuNC modified with two targeting ligands for tumor targeted imaging, but also confirm the promising future of dual targeting AuNC as a core for the design of prodrug in the field of cancer therapy.