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Biological and Medical Applications of Materials and Interfaces
Macrophages-mediated Delivery of Small Gold Nanorods for Tumor Hypoxia Photoacoustic Imaging and Enhanced Photothermal Therapy Lu An, Yuanyuan Wang, Jiaomin Lin, Qiwei Tian, Yinxiao Xie, Junqing Hu, and Shi-Ping Yang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.9b00495 • Publication Date (Web): 08 Apr 2019 Downloaded from http://pubs.acs.org on April 8, 2019
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ACS Applied Materials & Interfaces
Macrophages-mediated Delivery of Small Gold Nanorods for Tumor Hypoxia Photoacoustic Imaging and Enhanced Photothermal Therapy Lu An, †, a Yuanyuan Wang, †, a Jiaomin Lin, a Qiwei Tian,*, a Yinxiao Xie, a Junqing Hu, b and Shiping Yang *, a a
The Key Laboratory of Resource Chemistry of the Ministry of Education, the Shanghai Key
Laboratory of Rare Earth Functional Materials, and the Shanghai Municipal Education Committee Key Laboratory of Molecular Imaging Probes and Sensors, Shanghai Normal University, Shanghai 200234, China. b
College of Health Science and Environmental Engineering, Shenzhen Technology University,
Shenzhen 518118, China. KEYWORDS: macrophages, gold nanorods, hypoxia, photoacoustic imaging, photothermal therapy
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ABSTRACT: Macrophage-mediated delivery of drugs or nanoparticles has great potential in cancer treatment because it can avoid interception by the immune system and cross the bloodvessel barriers to reach the hypoxic regions of tumors. However, macrophage based delivery systerm still face some great challenge, such as low theranostics agent loading capacity, and hypoxic regions tendency in vivo. Herein, small gold nanorods (AuNRs) was used as the model theranostics agent for design a macrophage-mediated delivery systerm with high loading quantity for tumor hypoxia photoacoustic (PA) imaging and enhanced photothermal therapy (PTT). AuNRs modified with various thiolated polyethylene glycols (HS-PEG) via ligand exchange were investigated for toxicity and cell uptake by macrophages. The macrophage-loaded AnionicAuNRs (Anionic-AuNRs@RAW) for tumor hypoxic regions tendency were verified by in vivo PA imaging and tumor sections. In vivo systemic PTT demonstrated enhanced tumor inhibition of Anionic-AuNRs@RAW. This macrophage-mediated delivery system with high loading capacity could be used to enhance the effectiveness of cancer treatment.
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ACS Applied Materials & Interfaces
1. INTRODUCTION Despite decades of intensive research, the increasing incidence and high mortality of cancer continue to present great challenges to cancer treatment. In solid tumors, tumor cells grow much faster than that of internal blood vessels, and the partial pressure of oxygen of local tumor tissue is decreased, thereby producing non-vascularized anoxic regions in solid tumors (hypoxic regions).1-3 Tumor susceptibility to anticancer drugs, radiation and free radicals is reduced due to hypoxic regions in tumors. This phenomenon results in tumor neovascularization and production of hypoxia-induction factors (HIFs) as well as the recurrence, invasion and metastasis of tumor cells and eventually to treatment failure.4, 5 Various strategies have been proposed for the treatment of hypoxic regions in tumors to improve therapeutic outcomes6: hyperbaric oxygen therapy;7 filling oxygen-rich gas into therapeutic agents;8, generation ability;10, agents;12,
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aerobic therapeutic agents with oxygen-
combination of hypoxia-activated prodrugs and oxygenated therapeutic
tumor hypoxia-targeted drug carriers;14 anaerobic bacteria or viruses15 and so on.
However, it remains a great challenge to further improve the treatment efficiency. Recently, delivery systems based on cell-mediated drugs or nanoparticles, such as macrophages,16 lymphocytes,17 neutrophils18 or stem cells,19 have attracted great attention for several advantages. One advantage is that they can cross almost impermeable biologic barriers to reach tumor regions.20 In this way, they provide an opportunity to “conceal” therapeutic agents to weaken immunogenicity and toxicity to prolong the circulation of drugs or nanomaterials in vivo.21 Among them, macrophages, such as primary bone marrow macrophages and mouse macrophages (RAW264.7 cells),
have been demonstrated to migrate to the hypoxic regions of tumors and can
serve as a “Trojan Horse” delivery vector to transport nanoparticles to improve therapeutic effects
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due to the innate phagocytic ability.22-26 However, this delivery system still face some great challenge, such as low theranostics agent loading capacity, and hypoxic regions tendency in vivo. To simultaneously achieve high phagocytosis quantity of theranostics agent and visually observe hypoxic regions tendency of macrophages-mediated delivery system in vivo, we proposed a strategy, tunning the surface charge of nanoparticles to improve their uptake by cells, and track the hypoxic regions tendency of this delivery system in vivo by multispectral PA imaging, which can identify the hypoxic regions through monitor blood oxygenation in vessels and tissues.27-31 We demonstrated this design using small AuNRs as an model theranostics agent, which is the most attracted probe for bioapplications (e.g., PA imaging and PTT) due to its strong absorption in the near-infrared (NIR) region, good biocompatibility and easy functionalization.26,
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Herein,
AuNRs of length
