Letter Cite This: Nano Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/NanoLett
G‑Quadruplex-Based Nanoscale Coordination Polymers to Modulate Tumor Hypoxia and Achieve Nuclear-Targeted Drug Delivery for Enhanced Photodynamic Therapy Yu Yang,† Wenjun Zhu,‡ Liangzhu Feng,‡ Yu Chao,‡ Xuan Yi,§ Ziliang Dong,‡ Kai Yang,§ Weihong Tan,∥ Zhuang Liu,*,‡ and Meiwan Chen*,†
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State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, China ‡ Institute of Functional Nano & Soft Materials Laboratory (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China § School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, Jiangsu 215123, China ∥ Center for Research at Bio/Nano Interface, Department of Chemistry, Department of Physiology and Functional Genomics, Health Cancer Center, UF Genetics Institute, McKnight Brain Institute, University of Florida, Gainesville, Florida 32611, United States S Supporting Information *
ABSTRACT: Photodynamic therapy (PDT) is a lighttriggered therapy used to kill cancer cells by producing reactive oxygen species (ROS). Herein, a new kind of DNA nanostructure based on the coordination between calcium ions (Ca2+) and AS1411 DNA G quadruplexes to form nanoscale coordination polymers (NCPs) is developed via a simple method. Both chlorine e6 (Ce6), a photosensitizer, and hemin, an iron-containing porphyrin, can be inserted into the G-quadruplex structure in the obtained NCPs. With further polyethylene glycol (PEG) modification, we obtain Ca-AS1411/Ce6/hemin@pHis-PEG (CACH-PEG) NCP nanostructure that enables the intranuclear transport of photosensitizer Ce6 to generate ROS inside cell nuclei that are the most vulnerable to ROS. Meanwhile, the inhibition of antiapoptotic protein B-cell lymphoma 2 (Bcl-2) expression by AS1411 allows for greatly improved PDT-induced cell apoptosis. Furthermore, the catalase-mimicking DNAzyme function of G-quadruplexes and hemin in those NCPs could decompose tumor endogenous H2O2 to in situ generate oxygen so as to further enhance PDT by overcoming the hypoxia-associated resistance. This work develops a simple yet general method with which to fabricate DNA-based NCPs and presents an interesting concept of a nanoscale drug-delivery system that could achieve the intranuclear delivery of photosensitizers, the down-regulation of antiapoptotic proteins, and the modulation of the unfavorable tumor microenvironment simultaneously for improved cancer therapy. KEYWORDS: Nanoscale coordination-polymers, NCPs, G-quadruplex, DNA nanostructure, photodynamic therapy, tumor hypoxia
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by antagonizing release of mitochondrial cytochrome c to compensate cell apoptosis.7,8 Furthermore, owing to the insufficient oxygen supply within tumor microenvironment (TME),9 the hypoxia existing in solid tumors would lead to resistance of tumor cells to oxygen-involving PDT.10,11 Therefore, to optimize the therapeutic responses of tumors to PDT, it would be of great interest to exploit multifunctional nanoscale delivery systems to deliver photosensitizers directly into cell nuclei for more-effective DNA damage, down-regulate the tumor anti-apoptotic Bcl-2 protein expression, and promote
hotodynamic therapy (PDT) has been regarded as a safe and selective cancer treatment strategy that combines photosensitizing agents, light, and tissue oxygen to have a cytotoxic effect on cancer cells.1−3 During PDT, the generation of singlet oxygen (SO) and reactive oxygen species (ROS) by photosensitizers under light irradiation could lead to DNA damage and cell apoptosis.4,5 Owing to the extremely short lifespan (
