Article pubs.acs.org/cm
Core−Shell Metal-Organic Frameworks as Fe2+ Suppliers for Fe2+Mediated Cancer Therapy under Multimodality Imaging Dongdong Wang,†,⊥ Jiajia Zhou,§,⊥ Ruhui Chen,† Ruohong Shi,† Changlai Wang,† Jian Lu,† Gaozheng Zhao,† Guoliang Xia,† Shu Zhou,§ Zhenbang Liu,§ Haibao Wang,*,‡ Zhen Guo,*,§ and Qianwang Chen*,† †
Hefei National Laboratory for Physical Sciences at Microscale, Department of Materials Science & Engineering & Collaborative Innovation Center of Suzhou Nano Science and Technology, CAS High Magnetic Field Laboratory, University of Science and Technology of China, Hefei, 230026, China § Anhui Key Laboratory for Cellular Dynamics and Chemical Biology, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China ‡ Radiology Department of the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China S Supporting Information *
ABSTRACT: Integrated theranostic agents can provide comprehensive and efficient tools for simultaneous cancer diagnosis and therapy; however, limitations on efficiency and safety offer great room for improvement. Artesunate (AS), as an iron-dependent drug, has been investigated in cancer therapy, depending on free-radical generation for its action, which may reduce side effects commonly associated with conventional chemotherapy agents with low selectivity to target tumors. However, rapid clearance of its free form and limited availability of Fe ion in tumor sites become the main bottlenecks in cancer therapy. Herein, core−shell Mn3[Co(CN)6]2@MIL-100(Fe) metal-organic frameworks (CS-MOFs) nanocube was designed using a layer-by-layer method, which holds great potential for synchronous co-delivery of AS and ferric ions for cancer therapy. Moreover, the heterogeneous hybrid CS-MOFs show single- and two-photon fluorescence, together with T2 and enhanced T1 magnetic resonance imaging ability. pH-responsive degradation of CS-MOFs enables on-demand Fe(III) and AS release in the tumor microenvironment. The intracellular ferric ions will further be reduced to ferrous ion that catalyze AS to generate carbon-centered free radicals and reactive oxygen species (ROS). The potential of this alternative antitumor modality under multimodality imaging is demonstrated both in vitro and in vivo. In addition, compared with free AS alone, the nanodrug system CS-MOFs@AS shows significantly enhanced tumor delivery specificity and negligible long-term toxicity. In vivo therapy results indicate that the antitumor efficacy of CS-MOFs@AS was 5.79 times greater than that of free AS, making it a promising Fe2+-mediated drugs delivery system.
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INTRODUCTION Porous metal−organic frameworks (MOFs) have numerous potential applications in gas storage and separation,1,2 catalysis,3,4 biomedical diagnosis,5 and drug delivery,6,7 because of their excellent intrinsic properties, such as large pore volume and large surface area, together with tunable pore size.8,9 When the particle size is reduced down to the nanoscale level, nanoMOFs (NMOFs) show potential for biomedical applications such as serving as ideal vehicles with high drug-loading capacity and controllable drug-release profiles, and magnetic resonance imaging (MRI) contrast agents with good biocompatibility and biodegradability.10−12 Theranostics that integrate diagnostic and therapeutic moieties into one single platform can provide comprehensive and efficient tools for simultaneous diagnosis and therapy of cancer since its introduction by John Funkhouser, the Chief Executive Officer of PharmaNetics in 1998. Particularly, smart hybrid nanosystems with the © 2017 American Chemical Society
adaptability and responsiveness to external stimuli (such as physical stimuli (light, temperature, magnetic field) and physiological stimuli (pH, enzymes)) can enhance the enrichment of therapeutic agents through on-demand cargo release in the tumor region, thus improving the therapeutic efficacy. The integration of therapeutic capability and diagnostic ability into one simple system is highly useful in cargo delivery, invasive image-guided therapy, and so on. Recently, NMOFs based on nontoxic and biodegradable porous iron(III) carboxylate materials with different compositions and structures (for example, the MIL family, MIL-88A(Fe), MIL-100(Fe), MIL-101(Fe), where MIL represents Materials of Institut Received: December 9, 2016 Revised: March 31, 2017 Published: April 3, 2017 3477
DOI: 10.1021/acs.chemmater.6b05215 Chem. Mater. 2017, 29, 3477−3489
Article
Chemistry of Materials
Scheme 1. Anticancer Mechanism of AS-Loaded CS-MOFs: (a) Fabrication of CS-MOFs and Loading of Anticancer Drug AS through the Pores of MOFs and the CS-MOFs@AS Was Obtained, and (b) the Endocytosis of CS-MOFs@AS Nanocubes by HeLa Cell:Fe(III) and AS are Co-Released due to the pH-Responsive Degradation of Outer S-MOFs (the Transformation of Fe(III) to Fe(II) through Iron Reductase and Other Reductive Agents; Fe(II) React with AS To Generate Carbon-Centered Free Radicalsa
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The generation of carbon-centered free radicals induces an increase of ROS level, as well as the death of cancer cells.
us with valuable resources for anticancer drugs, such as paclitaxel and camptothecin, while insufficient reserves and exorbitant prices hamper their application.21 Artesunate (AS), which is a partially synthetic derivative of the naturally occurring endoperoxide antimalarial artemisinin, has shown profound cytotoxicity against various tumor cells in vitro and in vivo over the past 10 years. Two ferrous ion-related anticancer mechanisms have been proposed: one is reductive scission of the peroxide bridge to generate carbon-centered radicals, the other is the Fenton-reaction-related production of hydroperoxide or hydroxyl radicals.22−24 However, two main factors have hindered the potential application of AS as an antitumor drug. One limiting factor is that intravenous injection of AS is often associated with high initial concentration and often suffers from rapid half-life estimates (
