FULL PAPER www.afm-journal.de © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1804901 (1 of 11) Covalent Organic Polymers Based on Fluorinated Porphyrin as Oxygen Nanoshuttles for Tumor Hypoxia Relief and Enhanced Photodynamic Therapy Danlei Tao, Liangzhu Feng,* Yu Chao, Chao Liang, Xuejiao Song, Hairong Wang, Kai Yang, and Zhuang Liu* Effective and sustained tumor oxygenation has found practical significance in benefiting the treatment of solid tumors. In this study, fluorinated covalent organic polymers (COPs) are prepared by cross- linking the photosensitizer meso-5, 10, 15, 20-tetra (4-hydroxylphenyl) porphyrin (THPP) with perfluorosebacic acid (PFSEA) and poly(ethylene glycol) (PEG) via a one-pot esterification, to enable simultaneous tumor oxygenation and photodynamic treatment. Due to the presence of PFSEA, the obtained THPP pf –PEG shows efficient loading of perfluoro-15-crown- 5-ether (PFCE), a type of perfluocarbon, and thereby molecular oxygen, both of which would significantly enhance the photodynamic effect of THPP. After chelating THPP with a radio-isotope, 99m Tc, both THPP pf – PEG and PFCE-loaded THPP pf –PEG (PFCE@THPP pf –PEG) can be vividly visualized under the single-photon emission computed tomography (SPECT) imaging, which uncovers efficient tumor accumulation of those COPs’ post intravenous injection. Owing to the oxygen delivery ability of PFCE, efficient tumor oxygenation is observed for mice post injection of PFCE@THPP pf –PEG, which further leads to greatly enhanced photodynamic treatment of tumors. This study presents a unique type of multifunctional fluorinated COPs with well-defined composition, long blood circulation time, and sustained tumor oxygenation ability, showing great promises for potential clinical translation in photodynamic treatment of tumors. DOI: 10.1002/adfm.201804901 D. L. Tao, Dr. L. Z. Feng, Y. Chao, C. Liang, Dr. X. J. Song, Dr. H. R. Wang, Prof. Z. Liu Institute of Functional Nano and Soft Materials (FUNSOM) Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices Soochow University Suzhou 215123, China E-mail: lzfeng@suda.edu.cn; zliu@suda.edu.cn Dr. K. Yang School of Radiation Medicine and Protection and School for Radiological and Interdisciplinary Sciences (RAD-X) Medical College of Soochow University Suzhou 215123, China The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adfm.201804901. 1. Introduction Tumor hypoxia, featured with limited oxygen levels inside the solid tumors, has been found to be one of the hostile charac- teristics of solid tumors to promote tumor progression and metastasis. [1] Meanwhile, it has been widely recognized that hypoxia would also severely impair the treatment outcomes for several cancer therapies, especially those that demand oxygen to kill tumor cells. [2–4] In recent decades, photo- dynamic therapy (PDT), which utilizes the oxygen reactive oxygen species (ROSs) pro- duced from the molecular oxygen in the presence of photosensitizers and suitable excitation lights, has shown to be an effec- tive method for cancer treatments as shown in both preclinical and clinical studies. [5–7] However, the tumor hypoxia would remark- ably compromise the therapeutic efficacy of PDT as a result of insufficient oxygen supply during the PDT treatment. [8,9] There- fore, tumor hypoxia has recently been inten- sively explored and shown to be a promising target for improved cancer therapy. In the past several years, there have been a number of different intriguing strategies designed for efficient tumor hypoxia atten- uation to enable enhanced cancer treatment. [4,10–12] It has been shown that the increased tumor blood perfusion via boosting the tumor blood flow through the mild hypothermia effect, or nor- malization of tumor vasculatures, could lead to efficient tumor oxygenation. [13,14] In addition, in situ production of O 2 from the decomposition of endogenous H 2 O 2 inside tumors with cata- lase or manganese dioxides containing nanostructures has also been evidenced to be effective for tumor hypoxia attenuation and favorable for the subsequent cancer treatment. [15–17] Moreover, several different oxygen nanoshuttles have been developed to enable direct tumor-targeted delivery of oxygen for tumor hypoxia relief. [18–20] In particular, nanodroplets of perfluorocarbon (PFC) with great biocompatibility and high solubility of oxygen have been found to be extremely useful as oxygen delivery carriers to allow effective tumor oxygenation and enhanced cancer PDT, as demonstrated by our and others’ recent reports. [10,21,22] Cancer Therapy Adv. Funct. Mater. 2018, 1804901