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    Hyperthermia and Controllable Free Radical Coenhanced Synergistic Therapy in Hypoxia Enabled by Near-Infrared-II Light Irradiation. Yang Jun,Xie Rui,Feng Lili,Liu Bin,Lv Ruichan,Li Chunxia,Gai Shili,He Fei,Yang Piaoping,Lin Jun ACS nano Tumor cell metabolism and tumor blood vessel proliferation are distinct from normal cells. The resulting tumor microenvironment presents a characteristic of hypoxia, which greatly limits the generation of oxygen free radicals and affects the therapeutic effect of photodynamic therapy. Here, we developed an oxygen-independent free radical generated nanosystem (CuFeSe-AIPH@BSA) with dual-peak absorption in both near-infrared (NIR) regions and utilized it for imaging-guided synergistic treatment. The special absorption provides the nanosystem with high photothermal conversion efficiency and favorably matched photoactivity in both I and II NIR biological windows. Upon NIR light irradiation, the generated heat could prompt AIPH release and decompose to produce oxygen-independent free radicals for killing cancer cells effectively. The contrastive research results show that the enhanced therapeutic efficacy of NIR-II over NIR-I is principally due to its deeper tissue penetration and higher maximum permission exposure that benefits from a longer wavelength. Hyperthermia effect and the production of toxic free radicals upon NIR-II laser illumination are extremely effective in triggering apoptosis and death of cancer cells in the tumor hypoxia microenvironment. The high biocompatibility and excellent anticancer efficiency of CuFeSe-AIPH@BSA allow it to be an ideal oxygen-independent nanosystem for imaging-guided and NIR-II-mediated synergistic therapy systemic administration. 10.1021/acsnano.9b05985
    Bacteria-Mediated Hypoxia-Specific Delivery of Nanoparticles for Tumors Imaging and Therapy. Luo Cheng-Hung,Huang Chih-Ting,Su Chia-Hao,Yeh Chen-Sheng Nano letters The hypoxia region in a solid tumor has been recognized as a complex microenvironment revealing very low oxygen concentration and deficient nutrients. The hypoxic environment reduces the susceptibility of the cancer cells to anticancer drugs, low response of free radicals, and less proliferation of cancer cells in the center of the solid tumors. However, the reduced oxygen surroundings provide an appreciable habitat for anaerobic bacteria to colonize. Here, we present the bacteria-mediated targeting hypoxia to offer the expandable spectra for diagnosis and therapy in cancer diseases. Two delivery approaches involving a cargo-carrying method and an antibody-directed method were designed to deliver upconversion nanorods for imaging and Au nanorods for photothermal ablation upon near-infrared light excitation for two forms of the anaerobic Bifidobacterium breve and Clostridium difficile. The antibody-directed strategy shows the most effective treatment giving stronger imaging and longer retention period and effective therapy to completely remove tumors. 10.1021/acs.nanolett.6b00262
    Polyoxometalate-Based Radiosensitization Platform for Treating Hypoxic Tumors by Attenuating Radioresistance and Enhancing Radiation Response. Yong Yuan,Zhang Chunfang,Gu Zhanjun,Du Jiangfeng,Guo Zhao,Dong Xinghua,Xie Jiani,Zhang Guangjin,Liu Xiangfeng,Zhao Yuliang ACS nano Radioresistance is one of the undesirable impediments in hypoxic tumors, which sharply diminishes the therapeutic effectiveness of radiotherapy and eventually results in the failure of their treatments. An attractive strategy for attenuating radioresistance is developing an ideal radiosensitization system with appreciable radiosensitization capacity to attenuate tumor hypoxia and reinforce radiotherapy response in hypoxic tumors. Therefore, we describe the development of Gd-containing polyoxometalates-conjugated chitosan (GdW@CS nanosphere) as a radiosensitization system for simultaneous extrinsic and intrinsic radiosensitization, by generating an overabundance of cytotoxic reactive oxygen species (ROS) using high-energy X-ray stimulation and mediating the hypoxia-inducible factor-1a (HIF-1a) siRNA to down-regulate HIF-1α expression and suppress broken double-stranded DNA self-healing. Most importantly, the GdW@CS nanospheres have the capacity to promote the exhaustion of intracellular glutathione (reduced GSH) by synergy W-triggered GSH oxidation for sufficient ROS generation, thereby facilitating the therapeutic efficiency of radiotherapy. As a result, the as-synthesized GdW@CS nanosphere can overcome radioresistance of hypoxic tumors through a simultaneous extrinsic and intrinsic strategy to improve radiosensitivity. We have demonstrated GdW@CS nanospheres with special radiosensitization behavior, which provides a versatile approach to solve the critical radioresistance issue of hypoxic tumors. 10.1021/acsnano.7b03037
    Hypoxia-Irrelevant Photonic Thermodynamic Cancer Nanomedicine. Xiang Huijing,Lin Han,Yu Luodan,Chen Yu ACS nano The hypoxic tumor microenvironment severely lowers the therapeutic efficacy of oxygen-dependent anticancer modalities because tumor hypoxia hinders the generation of toxic reactive oxygen species. Here we report a thermodynamic cancer-therapeutic modality that employs oxygen-irrelevant free radicals generated from thermo-labile initiators for inducing cancer cell death. A free radical nanogenerator was engineered via direct growth of mesoporous silica layer onto the surface of two-dimensional NbC MXene nanosheets toward multifunctionality, where the mesopore provided the reservoirs for initiators and the MXene core acted as the photonic-thermal trigger at the near-infrared-II biowindow (NIR-II). Upon illumination by a 1064 nm NIR-II laser, the photothermal-conversion effect of NbC MXene induced the fast release and quick decomposition of the encapsulated initiators (AIPH) to produce free radicals, which promoted cancer cell apoptosis in both normoxic and hypoxic microenvironment. Systematic in vitro and in vivo evaluations have demonstrated the synergistic-therapeutic outcome of this intriguing photonic nanoplatform-enabled thermodynamic cancer therapy for completely eradicating the 4T1 tumors without recurrence by NIR-II laser irradiation. This work pioneers the thermodynamic therapy for oxygen-independent cancer treatment by photonic triggering at the NIR-II biowindow. 10.1021/acsnano.8b08910
    Tumor Reoxygenation and Blood Perfusion Enhanced Photodynamic Therapy using Ultrathin Graphdiyne Oxide Nanosheets. Jiang Wei,Zhang Zhen,Wang Qin,Dou Jiaxiang,Zhao Yangyang,Ma Yinchu,Liu Huarong,Xu Hangxun,Wang Yucai Nano letters Both diffusion-limited and perfusion-limited hypoxia are associated with tumor progression, metastasis, and the resistance to therapeutic modalities. A strategy that can efficiently overcome both types of hypoxia to enhance the efficacy of cancer treatment has not been reported yet. Here, it is shown that by using biomimetic ultrathin graphdiyne oxide (GDYO) nanosheets, both types of hypoxia can be simultaneously addressed toward an ideal photodynamic therapy (PDT). The GDYO nanosheets, which are oxidized and exfoliated from graphdiyne (GDY), are able to efficiently catalyze water oxidation to release O and generate singlet oxygen (O) using near-infrared irradiation. Meanwhile, GDYO nanosheets also exhibit excellent light-to-heat conversion performance with a photothermal conversion efficiency of 60.8%. Thus, after the GDYO nanosheets are coated with iRGD peptide-modified red blood membrane (i-RBM) to achieve tumor targeting, the biomimetic GDYO@i-RBM nanosheets can simultaneously enhance tumor reoxygenation and blood perfusion for PDT. This study provides new insights into utilizing novel water-splitting materials to relieve both diffusion- and perfusion-limited hypoxia for the development of a novel therapeutic platform. 10.1021/acs.nanolett.9b01458
    Hypoxia-Targeting, Tumor Microenvironment Responsive Nanocluster Bomb for Radical-Enhanced Radiotherapy. Huo Da,Liu Sen,Zhang Chao,He Jian,Zhou Zhengyang,Zhang Hao,Hu Yong ACS nano Although ultrasmall metal nanoparticles (NPs) have been used as radiosensitizers to enhance the local damage to tumor tissues while reducing injury to the surrounding organs, their rapid clearance from the circulatory system and the presence of hypoxia within the tumor continue to hamper their further application in radiotherapy (RT). In this study, we report a size tunable nanocluster bomb with a initial size of approximately 33 nm featuring a long half-life during blood circulation and destructed to release small hypoxia microenvironment-targeting NPs (∼5 nm) to achieve deep tumor penetration. Hypoxic profiles of solid tumors were precisely imaged using NP-enhanced computed tomography (CT) with higher spatial resolution. Once irradiated with a 1064 nm laser, CT-guided, local photothermal ablation of the tumor and production of radical species could be achieved simultaneously. The induced radical species alleviated the hypoxia-induced resistance and sensitized the tumor to the killing efficacy of radiation in Akt-mTOR pathway-dependent manner. The therapeutic outcome was assessed in animal models of orthotopical breast cancer and pancreatic cancer, supporting the feasibility of our combinational treatment in hypoxic tumor management. 10.1021/acsnano.7b04737
    Tumor-Penetrating Nanoparticles for Enhanced Anticancer Activity of Combined Photodynamic and Hypoxia-Activated Therapy. Wang Yazhe,Xie Ying,Li Jing,Peng Zheng-Hong,Sheinin Yuri,Zhou Jianping,Oupický David ACS nano Poor tumor penetration is a major challenge for the use of nanoparticles in anticancer therapy. Moreover, the inability to reach hypoxic tumor cells that are distant from blood vessels results in inadequate exposure to antitumor therapeutics and contributes to development of chemoresistance and increased metastasis. In the present study, we developed iRGD-modified nanoparticles for simultaneous tumor delivery of a photosensitizer indocyanine green (ICG) and hypoxia-activated prodrug tirapazamine (TPZ). The iRGD-modified nanoparticles loaded with ICG and TPZ showed significantly improved penetration in both 3D tumor spheroids in vitro and orthotopic breast tumors in vivo. ICG-mediated photodynamic therapy upon irradiation with a near-IR laser induced hypoxia, which activated antitumor activity of the codelivered TPZ for synergistic cell-killing effect. In vivo studies demonstrated that the nanoparticles could efficiently deliver the drug combination in 4T1 orthotopic tumors. Primary tumor growth and metastasis were effectively inhibited by the iRGD-modified combination nanoparticles with minimal side effects. The results also showed the anticancer benefits of codelivering ICG and TPZ in a single nanoparticle formulation in contrast to a mixture of nanoparticles containing individual drugs. The study demonstrates the benefits of combining tumor-penetrating nanoparticles with hypoxia-activated drug treatment and establishes a delivery platform for PDT and hypoxia-activated chemotherapy. 10.1021/acsnano.6b08731
    The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia. Ashton Thomas M,Fokas Emmanouil,Kunz-Schughart Leoni A,Folkes Lisa K,Anbalagan Selvakumar,Huether Melanie,Kelly Catherine J,Pirovano Giacomo,Buffa Francesca M,Hammond Ester M,Stratford Michael,Muschel Ruth J,Higgins Geoff S,McKenna William Gillies Nature communications Tumour hypoxia renders cancer cells resistant to cancer therapy, resulting in markedly worse clinical outcomes. To find clinical candidate compounds that reduce hypoxia in tumours, we conduct a high-throughput screen for oxygen consumption rate (OCR) reduction and identify a number of drugs with this property. For this study we focus on the anti-malarial, atovaquone. Atovaquone rapidly decreases the OCR by more than 80% in a wide range of cancer cell lines at pharmacological concentrations. In addition, atovaquone eradicates hypoxia in FaDu, HCT116 and H1299 spheroids. Similarly, it reduces hypoxia in FaDu and HCT116 xenografts in nude mice, and causes a significant tumour growth delay when combined with radiation. Atovaquone is a ubiquinone analogue, and decreases the OCR by inhibiting mitochondrial complex III. We are now undertaking clinical studies to assess whether atovaquone reduces tumour hypoxia in patients, thereby increasing the efficacy of radiotherapy. 10.1038/ncomms12308
    Gold Cube-in-Cube Based Oxygen Nanogenerator: A Theranostic Nanoplatform for Modulating Tumor Microenvironment for Precise Chemo-Phototherapy and Multimodal Imaging. Zhang Xing,Xi Zhongqian,Machuki Jeremiah Ong'achwa,Luo Jianjun,Yang Dongzhi,Li Jingjing,Cai Weibing,Yang Yun,Zhang Lijie,Tian Jiangwei,Guo Kaijin,Yu Yanyan,Gao Fenglei ACS nano Engineering a versatile oncotherapy nanoplatform integrating both diagnostic and therapeutic functions has always been an intractable challenge in targeted cancer treatment. Herein, to actualize the theme of precise medicine, a nanoplatform is developed by anchoring Mn-Cdots to doxorubicin (DOX)-loaded mesoporous silica-coated gold cube-in-cubes core/shell nanocomposites and further conjugating them to a Arg-Gly-Asp (RGD) peptide (denoted as RGD-CCmMC/DOX) to achieve an active-targeting effect. Under 635 nm irradiation, the nanoplatform acts as oxygen nanogenerator that produces O in situ and amplifies the content of singlet oxygen (O) in the hypoxic tumor microenvironment (TME), which has been demonstrated to attenuate tumor hypoxia and synchronously enhance photodynamic efficacy. Moreover, the gold cube-in-cube core in this work has been proven as a photothermal agent for hyperthermia, which exhibits a favorable photothermal effect with a 65.6% calculated photothermal conversion efficiency under 808 nm irradiation. In addition, the nanoplatform achieves heat- and pH-sensitive drug release with precise control to specific-tumor sites, executing combined chemo-phototherapy functions. Besides, it functions as a multimodal bioimaging agent of photothermal, fluorescence, and magnetic resonance imaging for the accurate diagnosis and guidance of therapy. As validated by in vivo and in vitro assays, the TME-responsive nanoplatform is highly biocompatible and effectively obliterates 4T1 tumor xenografts on nude mice after triple-synergetic treatment. This work presents a rational design of versatile nanoplatforms, which modulate the TME to enable high therapeutic performance and multiplexed imaging, which provides an innovative paradigm for targeted tumor therapy. 10.1021/acsnano.8b09786
    Fate-mapping post-hypoxic tumor cells reveals a ROS-resistant phenotype that promotes metastasis. Godet Inês,Shin Yu Jung,Ju Julia A,Ye I Chae,Wang Guannan,Gilkes Daniele M Nature communications Hypoxia is known to be detrimental in cancer and contributes to its development. In this work, we present an approach to fate-map hypoxic cells in vivo in order to determine their cellular response to physiological O gradients as well as to quantify their contribution to metastatic spread. We demonstrate the ability of the system to fate-map hypoxic cells in 2D, and in 3D spheroids and organoids. We identify distinct gene expression patterns in cells that experienced intratumoral hypoxia in vivo compared to cells exposed to hypoxia in vitro. The intratumoral hypoxia gene-signature is a better prognostic indicator for distant metastasis-free survival. Post-hypoxic tumor cells have an ROS-resistant phenotype that provides a survival advantage in the bloodstream and promotes their ability to establish overt metastasis. Post-hypoxic cells retain an increase in the expression of a subset of hypoxia-inducible genes at the metastatic site, suggesting the possibility of a 'hypoxic memory.' 10.1038/s41467-019-12412-1
    Perfluorocarbon regulates the intratumoural environment to enhance hypoxia-based agent efficacy. Wang Wenguang,Cheng Yuhao,Yu Peng,Wang Haoran,Zhang Yue,Xu Haiheng,Ye Qingsong,Yuan Ahu,Hu Yiqiao,Wu Jinhui Nature communications Hypoxia-based agents (HBAs), such as anaerobic bacteria and bioreductive prodrugs, require both a permeable and hypoxic intratumoural environment to be fully effective. To solve this problem, herein, we report that perfluorocarbon nanoparticles (PNPs) can be used to create a long-lasting, penetrable and hypoxic tumour microenvironment for ensuring both the delivery and activation of subsequently administered HBAs. In addition to the increased permeability and enhanced hypoxia caused by the PNPs, the PNPs can be retained to further achieve the long-term inhibition of intratumoural O reperfusion while enhancing HBA accumulation for over 24 h. Therefore, perfluorocarbon materials may have great potential for reigniting clinical research on hypoxia-based drugs. 10.1038/s41467-019-09389-2
    Real-Time Imaging of Free Radicals for Mitochondria-Targeting Hypoxic Tumor Therapy. Wang Xiao-Qiang,Peng Mengyun,Li Chu-Xin,Zhang Yu,Zhang Mingkang,Tang Ying,Liu Miao-Deng,Xie Bo-Ru,Zhang Xian-Zheng Nano letters Free radicals have emerged as new-type and promising candidates for hypoxic tumor treatment, and further study of their therapeutic mechanism by real-time imaging is of great importance to explore their biomedical applications. Herein, we present a smart free-radical generator AuNC-V057-TPP for hypoxic tumor therapy; the AuNC-V057-TPP not only exhibits good therapeutic effect under both hypoxic and normoxic conditions but also can monitor the release of free radicals in real-time both in vitro and in vivo. What is more, with the mitochondria-targeting ability, the AuNC-V057-TPP is demonstrated with improved antitumor efficacy through enhanced free radical level in mitochondria, which leads to mitochondrial membrane damage and ATP production reduction and finally induces cancer cell apoptosis. 10.1021/acs.nanolett.8b02670
    Hypoxia-tropic Protein Nanocages for Modulation of Tumor- and Chemotherapy-Associated Hypoxia. Huang Xinglu,Zhuang Jie,Chung Seung Woo,Huang Buwei,Halpert Gilad,Negron Karina,Sun Xuanrong,Yang Jun,Oh Yumin,Hwang Paul M,Hanes Justin,Suk Jung Soo ACS nano Despite its central role in tumor progression and treatment resistance, poor vascularization that necessitates penetration of therapeutics through tumor extracellular matrix (ECM) constitutes a significant challenge to managing tumor hypoxia via conventional systemic treatment regimens. In addition, methods to target hypoxic tumor cells are lacking. Here, we discovered that human ferritin nanocages (FTn) possess an intrinsic ability to preferentially engage with hypoxic tumor tissues, in addition to normoxic tumor areas. We also developed a simple method of endowing FTn with spatially controlled "mosaic" surface poly(ethylene glycol) (PEG) coatings that facilitate deep penetration of FTn through ECM to reach hypoxic tumor tissues while retaining its inherent hypoxia-tropic property. Hypoxia-inhibiting agents systemically delivered via this surface-PEGylated FTn were readily accumulated in hypoxic tumor tissues, thereby providing significantly enhanced therapeutic benefits compared to the identical agents delivered in solution as a stand-alone therapy or an adjuvant to restore efficacy of conventional systemic chemotherapy. 10.1021/acsnano.8b05399
    Ultrasound Triggered Tumor Oxygenation with Oxygen-Shuttle Nanoperfluorocarbon to Overcome Hypoxia-Associated Resistance in Cancer Therapies. Song Xuejiao,Feng Liangzhu,Liang Chao,Yang Kai,Liu Zhuang Nano letters Tumor hypoxia is known to be one of critical reasons that limit the efficacy of cancer therapies, particularly photodynamic therapy (PDT) and radiotherapy (RT) in which oxygen is needed in the process of cancer cell destruction. Herein, taking advantages of the great biocompatibility and high oxygen dissolving ability of perfluorocarbon (PFC), we develop an innovative strategy to modulate the tumor hypoxic microenvironment using nano-PFC as an oxygen shuttle for ultrasound triggered tumor-specific delivery of oxygen. In our experiment, nanodroplets of PFC stabilized by albumin are intravenously injected into tumor-bearing mice under hyperoxic breathing. With a low-power clinically adapted ultrasound transducer applied on their tumor, PFC nanodroplets that adsorb oxygen in the lung would rapidly release oxygen in the tumor under ultrasound stimulation, and then circulate back into the lung for reoxygenation. Such repeated cycles would result in dramatically enhanced tumor oxygenation and thus remarkably improved therapeutic outcomes in both PDT and RT treatment of tumors. Importantly, our strategy may be applied for different types of tumor models. Hence, this work presents a simple strategy to promote tumor oxygenation with great efficiency using agents and instruments readily available in the clinic, so as to overcome the hypoxia-associated resistance in cancer treatment. 10.1021/acs.nanolett.6b02365
    Biodegradable Biomimic Copper/Manganese Silicate Nanospheres for Chemodynamic/Photodynamic Synergistic Therapy with Simultaneous Glutathione Depletion and Hypoxia Relief. Liu Conghui,Wang Dongdong,Zhang Shuyuan,Cheng Yaru,Yang Fan,Xing Yi,Xu Tailin,Dong Haifeng,Zhang Xueji ACS nano The integration of reactive oxygen species (ROS)-involved photodynamic therapy (PDT) and chemodynamic therapy (CDT) holds great promise for enhanced anticancer effects. Herein, we report biodegradable cancer cell membrane-coated mesoporous copper/manganese silicate nanospheres (mCMSNs) with homotypic targeting ability to the cancer cell lines and enhanced ROS generation through singlet oxygen (O) production and glutathione (GSH)-activated Fenton reaction, showing excellent CDT/PDT synergistic therapeutic effects. We demonstrate that mCMSNs are able to relieve the tumor hypoxia microenvironment by catalytic decomposition of endogenous HO to O and further react with O to produce toxic O with a 635 nm laser irradiation. GSH-triggered mCMSNs biodegradation can simultaneously generate Fenton-like Cu and Mn ions and deplete GSH for efficient hydroxyl radical (•OH) production. The specific recognition and homotypic targeting ability to the cancer cells were also revealed. Notably, relieving hypoxia and GSH depletion disrupts the tumor microenvironment (TME) and cellular antioxidant defense system, achieving exceptional cancer-targeting therapeutic effects in vitro and in vivo. The cancer cells growth was significantly inhibited. Moreover, the released Mn can also act as an advanced contrast agent for cancer magnetic resonance imaging (MRI). Thus, together with photosensitizers, Fenton agent provider and MRI contrast effects along with the modulating of the TME allow mCMSNs to realize MRI-monitored enhanced CDT/PDT synergistic therapy. It provides a paradigm to rationally design TME-responsive and ROS-involved therapeutic strategies based on a single polymetallic silicate nanomaterial with enhanced anticancer effects. 10.1021/acsnano.8b09387
    Theranostic Liposomes with Hypoxia-Activated Prodrug to Effectively Destruct Hypoxic Tumors Post-Photodynamic Therapy. Feng Liangzhu,Cheng Liang,Dong Ziliang,Tao Danlei,Barnhart Todd E,Cai Weibo,Chen Meiwan,Liu Zhuang ACS nano Photodynamic therapy (PDT), a noninvasive cancer therapeutic method triggered by light, would lead to severe tumor hypoxia after treatment. Utilizing a hypoxia-activated prodrug, AQ4N, which only shows toxicity to cancer cells under hypoxic environment, herein, a multipurpose liposome is prepared by encapsulating hydrophilic AQ4N and hydrophobic hexadecylamine conjugated chlorin e6 (hCe6), a photosensitizer, into its aqueous cavity and hydrophobic bilayer, respectively. After chelating a Cu isotope with Ce6, the obtained AQ4N-Cu-hCe6-liposome is demonstrated to be an effective imaging probe for in vivo positron emission tomography, which together with in vivo fluorescence and photoacoustic imaging uncovers efficient passive homing of those liposomes after intravenous injection. After being irradiated with the 660 nm light-emitting diode light, the tumor bearing mice with injection of AQ4N-hCe6-liposome show severe tumor hypoxia, which in turn would trigger activation of AQ4N, and finally contributes to remarkably improved cancer treatment outcomes via sequential PDT and hypoxia-activated chemotherapy. This work highlights a liposome-based theranostic nanomedicine that could utilize tumor hypoxia, a side effect of PDT, to trigger chemotherapy, resulting in greatly improved efficacy compared to conventional cancer PDT. 10.1021/acsnano.6b07525
    Smart Nanoreactors for pH-Responsive Tumor Homing, Mitochondria-Targeting, and Enhanced Photodynamic-Immunotherapy of Cancer. Yang Guangbao,Xu Ligeng,Xu Jun,Zhang Rui,Song Guosheng,Chao Yu,Feng Liangzhu,Han Fengxuan,Dong Ziliang,Li Bin,Liu Zhuang Nano letters Photodynamic therapy (PDT) is an oxygen-dependent light-triggered noninvasive therapeutic method showing many promising aspects in cancer treatment. For effective PDT, nanoscale carriers are often needed to realize tumor-targeted delivery of photosensitizers, which ideally should further target specific cell organelles that are most vulnerable to reactive oxygen species (ROS). Second, as oxygen is critical for PDT-induced cancer destruction, overcoming hypoxia existing in the majority of solid tumors is important for optimizing PDT efficacy. Furthermore, as PDT is a localized treatment method, achieving systemic antitumor therapeutic outcomes with PDT would have tremendous clinical values. Aiming at addressing the above challenges, we design a unique type of enzyme-encapsulated, photosensitizer-loaded hollow silica nanoparticles with rationally designed surface engineering as smart nanoreactors. Such nanoparticles with pH responsive surface coating show enhanced retention responding to the acidic tumor microenvironment and are able to further target mitochondria, the cellular organelle most sensitive to ROS. Meanwhile, decomposition of tumor endogenous HO triggered by those nanoreactors would lead to greatly relieved tumor hypoxia, further favoring in vivo PDT. Moreover, by combining our nanoparticle-based PDT with check-point-blockade therapy, systemic antitumor immune responses could be achieved to kill nonirradiated tumors 1-2 cm away, promising for metastasis inhibition. 10.1021/acs.nanolett.8b00040
    Intelligent Albumin-MnO2 Nanoparticles as pH-/H2 O2 -Responsive Dissociable Nanocarriers to Modulate Tumor Hypoxia for Effective Combination Therapy. Chen Qian,Feng Liangzhu,Liu Jingjing,Zhu Wenwen,Dong Ziliang,Wu Yifan,Liu Zhuang Advanced materials (Deerfield Beach, Fla.) A unique type of pH/H2 O2 dual-responsive intelligent nanoscale delivery system based on albumin-coated MnO2 is presented, which is capable of modulating the tumor microenvironment (TME) by relieving hypoxia. Additionally, TME-responsive size changes enable effective intratumor diffusion. A highly effective combined photodynamic and chemotherapy is realized with these nanoparticles in a mouse tumor model. 10.1002/adma.201601902
    Platelet-Mimicking Biotaxis Targeting Vasculature-Disrupted Tumors for Cascade Amplification of Hypoxia-Sensitive Therapy. Zhang Mingkang,Ye Jing-Jie,Xia Yu,Wang Zi-Yang,Li Chu-Xin,Wang Xiao-Shuang,Yu Wuyang,Song Wen,Feng Jun,Zhang Xian-Zheng ACS nano Tumorous vasculature plays key roles in sustaining tumor growth. Vascular disruption is accompanied by internal coagulation along with platelet recruitment and the resulting suppression of oxygen supply. We intend to artificially create this physiological process to establish the mutual feedback between vascular disruption and platelet-mimicking biotaxis for the cascade amplification of hypoxia-dependent therapy. To prove this concept, mesoporous silica nanoparticles are co-loaded with a hypoxia-activated prodrug (HAP) and a vessel-disruptive agent and then coated with platelet membranes. Upon entering into tumors, our nanotherapeutic can disrupt local vasculature for tumor inhibition. This platelet membrane-coated nanoplatform shares the hemorrhage-tropic function with parental platelets and can be persistently recruited by the vasculature-disrupted tumors. In this way, the intratumoral vascular disruption and tumor targeting are biologically interdependent and mutually reinforced. Relying on this mutual feedback, tumorous hypoxia was largely promoted by more than 20-fold, accounting for the effective recovery of the HAP's cytotoxicity. Consequently, our bioinspired nanodesign has demonstrated highly specific and effective antitumor potency the biologically driven cooperation among intratumoral vascular disruption, platelet-mimicking biotaxis, cascade hypoxia amplification, and hypoxia-sensitive chemotherapy. This study offers a paradigm of correlating the therapeutic design with the physiologically occurring events to achieve better therapy performance. 10.1021/acsnano.9b07330
    Intelligent Albumin-MnO Nanoparticles as pH-/H O -Responsive Dissociable Nanocarriers to Modulate Tumor Hypoxia for Effective Combination Therapy. Chen Qian,Feng Liangzhu,Liu Jingjing,Zhu Wenwen,Dong Ziliang,Wu Yifan,Liu Zhuang Advanced materials (Deerfield Beach, Fla.) 10.1002/adma.201707414
    Self-Supplied Tumor Oxygenation through Separated Liposomal Delivery of HO and Catalase for Enhanced Radio-Immunotherapy of Cancer. Song Xuejiao,Xu Jun,Liang Chao,Chao Yu,Jin Qiutong,Wang Chao,Chen Meiwan,Liu Zhuang Nano letters The recent years have witnessed the blooming of cancer immunotherapy, as well as their combinational use together with other existing cancer treatment techniques including radiotherapy. However, hypoxia is one of several causes of the immunosuppressive tumor microenvironment (TME). Herein, we develop an innovative strategy to relieve tumor hypoxia by delivering exogenous HO into tumors and the subsequent catalase-triggered HO decomposition. In our experiment, HO and catalase are separately loaded within stealthy liposomes. After intravenous (iv) preinjection of CAT@liposome, another dose of HO@liposome is injected 4 h later. The sustainably released HO could be decomposed by CAT@liposome, resulting in a long lasting effect in tumor oxygenation enhancement. As the result, the combination treatment by CAT@liposome plus HO@liposome offers remarkably enhanced therapeutic effects in cancer radiotherapy as observed in a mouse tumor model as well as a more clinically relevant patient-derived xenograft tumor model. Moreover, the relieved tumor hypoxia would reverse the immunosuppressive TME to favor antitumor immunities, further enhancing the combined radio-immunotherapy with cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade. This work presents a simple yet effective strategy to promote tumor oxygenation via sequential delivering catalase and exogenous HO into tumors using well-established liposomal carriers, showing great potential for clinical translation in radio-immunotherapy of cancer. 10.1021/acs.nanolett.8b02720
    A Hypoxia-Responsive Albumin-Based Nanosystem for Deep Tumor Penetration and Excellent Therapeutic Efficacy. Yang Guangbao,Phua Soo Zeng Fiona,Lim Wei Qi,Zhang Rui,Feng Liangzhu,Liu Guofeng,Wu Hongwei,Bindra Anivind Kaur,Jana Deblin,Liu Zhuang,Zhao Yanli Advanced materials (Deerfield Beach, Fla.) Uncontrolled cancer cell proliferation, insufficient blood flow, and inadequate endogenous oxygen lead to hypoxia in tumor tissues. Herein, a unique type of hypoxia-responsive human serum albumin (HSA)-based nanosystem (HCHOA) is reported, prepared by cross-linking the hypoxia-sensitive azobenzene group between photosensitizer chlorin e6 (Ce6)-conjugated HSA (HC) and oxaliplatin prodrug-conjugated HSA (HO). The HCHOA nanosystem is stable under normal oxygen partial pressure with a size of 100-150 nm. When exposed to the hypoxic tumor microenvironment, the nanosystem can quickly dissociate into ultrasmall HC and HO therapeutic nanoparticles with a diameter smaller than 10 nm, significantly enabling their enhanced intratumoral penetration. After the dissociation, the quenched fluorescence of Ce6 in the produced HC nanoparticles can be recovered for bioimaging. At the same time, the production of singlet oxygen is increased because of the enhancement in the photoactivity of the photosensitizer. On account of these improvements, combined photodynamic therapy and chemotherapy is realized to display superior antitumor efficacy in vivo. Based on this simple strategy, it is possible to achieve the dissociation of hypoxic-responsive nanosystem to enhance the tumor penetration and therapeutic effect. 10.1002/adma.201901513
    O Economizer for Inhibiting Cell Respiration To Combat the Hypoxia Obstacle in Tumor Treatments. Yu Wuyang,Liu Tao,Zhang Mingkang,Wang Zixu,Ye Jingjie,Li Chu-Xin,Liu Wenlong,Li Runqing,Feng Jun,Zhang Xian-Zheng ACS nano Hypoxia, a ubiquitously aberrant phenomenon implicated in tumor growth, causes severe tumor resistance to therapeutic interventions. Instead of the currently prevalent solution through intratumoral oxygen supply, we put forward an "O-economizer" concept by inhibiting the O consumption of cell respiration to spare endogenous O and overcome the hypoxia barrier. A nitric oxide (NO) donor responsible for respiration inhibition and a photosensitizer for photodynamic therapy (PDT) are co-loaded into poly(d,l-lactide- co-glycolide) nanovesicles to provide a PDT-specific O economizer. Once accumulating in tumors and subsequently responding to the locally reductive environment, the carried NO donor undergoes breakdown to produce NO for inhibiting cellular respiration, allowing more O in tumor cells to support the profound enhancement of PDT. Depending on the biochemical reallocation of cellular oxygen resource, this O-economizer concept offers a way to address the important issue of hypoxia-induced tumor resistance to therapeutic interventions, including but not limited to PDT. 10.1021/acsnano.8b07852
    Selectively Potentiating Hypoxia Levels by Combretastatin A4 Nanomedicine: Toward Highly Enhanced Hypoxia-Activated Prodrug Tirapazamine Therapy for Metastatic Tumors. Yang Shengcai,Tang Zhaohui,Hu Chenyang,Zhang Dawei,Shen Na,Yu Haiyang,Chen Xuesi Advanced materials (Deerfield Beach, Fla.) Hypoxia-activated prodrugs (HAPs) have the potential to selectively kill hypoxic cells and convert tumor hypoxia from a problem to a selective treatment advantage. However, HAPs are unsuccessful in most clinical trials owing to inadequate hypoxia within the treated tumors, as implied by a further substudy of a phase II clinical trial. Here, a novel strategy for the combination of HAPs plus vascular disrupting agent (VDA) nanomedicine for efficacious solid tumor therapy is developed. An effective VDA nanomedicine of poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4 (CA4-NPs) is prepared and can selectively enhance tumor hypoxia and boost a typical HAP tirapazamine (TPZ) therapy against metastatic 4T1 breast tumors. After treatment with the combination of TPZ plus CA4-NPs, complete tumor reduction is observed in 4T1 xenograft mice (initial tumor volume is 180 mm ), and significant tumor shrinkage and antimetastatic effects are observed in challenging large tumors with initial volume of 500 mm . The report here highlights the potential of using a combination of HAPs plus VDA nanomedicine in solid tumor therapy. 10.1002/adma.201805955
    NIR-II Driven Plasmon-Enhanced Catalysis for a Timely Supply of Oxygen to Overcome Hypoxia-Induced Radiotherapy Tolerance. Yang Yue,Chen Mei,Wang Bingzhe,Wang Peng,Liu Yongchun,Zhao Yan,Li Kun,Song Guosheng,Zhang Xiao-Bing,Tan Weihong Angewandte Chemie (International ed. in English) Hypoxia, as a characteristic feature of solid tumor, can significantly adversely affect the outcomes of cancer radiotherapy (RT), photodynamic therapy, or chemotherapy. In this study, a strategy is developed to overcome tumor hypoxia-induced radiotherapy tolerance. Specifically, a novel two-dimensional Pd@Au bimetallic core-shell nanostructure (TPAN) was employed for the sustainable and robust production of O in long-term via the catalysis of endogenous H O . Notably, the catalytic activity of TPAN could be enhanced via surface plasmon resonance (SPR) effect triggered by NIR-II laser irradiation, to enhance the O production and thereby relieve tumor hypoxia. Thus, TPAN could enhance radiotherapy outcomes by three aspects: 1) NIR-II laser triggered SPR enhanced the catalysis of TPAN to produce O for relieving tumor hypoxia; 2) high-Z element effect arising from Au and Pd to capture X-ray energy within the tumor; and 3) TPAN affording X-ray, photoacoustic, and NIR-II laser derived photothermal imaging, for precisely guiding cancer therapy, so as to reduce the side effects from irradiation. 10.1002/anie.201906758
    G-Quadruplex-Based Nanoscale Coordination Polymers to Modulate Tumor Hypoxia and Achieve Nuclear-Targeted Drug Delivery for Enhanced Photodynamic Therapy. Yang Yu,Zhu Wenjun,Feng Liangzhu,Chao Yu,Yi Xuan,Dong Ziliang,Yang Kai,Tan Weihong,Liu Zhuang,Chen Meiwan Nano letters Photodynamic therapy (PDT) is a light-triggered 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 (Ca) 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 HO 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 anti-apoptotic proteins, and the modulation of the unfavorable tumor microenvironment simultaneously for improved cancer therapy. 10.1021/acs.nanolett.8b02732
    A Magnetofluorescent Carbon Dot Assembly as an Acidic H O -Driven Oxygenerator to Regulate Tumor Hypoxia for Simultaneous Bimodal Imaging and Enhanced Photodynamic Therapy. Jia Qingyan,Ge Jiechao,Liu Weimin,Zheng Xiuli,Chen Shiqing,Wen Yongmei,Zhang Hongyan,Wang Pengfei Advanced materials (Deerfield Beach, Fla.) Recent studies indicate that carbon dots (CDs) can efficiently generate singlet oxygen ( O ) for photodynamic therapy (PDT) of cancer. However, the hypoxic tumor microenvironment and rapid consumption of oxygen in the PDT process will severely limit therapeutic effects of CDs due to the oxygen-dependent PDT. Thus, it is becoming particularly important to develop a novel CD as an in situ tumor oxygenerator for overcoming hypoxia and substantially enhancing the PDT efficacy. Herein, for the first time, magnetofluorescent Mn-CDs are successfully prepared using manganese(II) phthalocyanine as a precursor. After cooperative self-assembly with DSPE-PEG, the obtained Mn-CD assembly can be applied as a smart contrast agent for both near-infrared fluorescence (FL) (maximum peak at 745 nm) and T -weighted magnetic resonance (MR) (relaxivity value of 6.97 mM s ) imaging. More interestingly, the Mn-CD assembly can not only effectively produce O (quantum yield of 0.40) but also highly catalyze H O to generate oxygen. These collective properties of the Mn-CD assembly enable it to be utilized as an acidic H O -driven oxygenerator to increase the oxygen concentration in hypoxic solid tumors for simultaneous bimodal FL/MR imaging and enhanced PDT. This work explores a new biomedical use of CDs and provides a versatile carbon nanomaterial candidate for multifunctional nanotheranostic applications. 10.1002/adma.201706090
    A Mesoporous Nanoenzyme Derived from Metal-Organic Frameworks with Endogenous Oxygen Generation to Alleviate Tumor Hypoxia for Significantly Enhanced Photodynamic Therapy. Wang Dongdong,Wu Huihui,Lim Wei Qi,Phua Soo Zeng Fiona,Xu Pengping,Chen Qianwang,Guo Zhen,Zhao Yanli Advanced materials (Deerfield Beach, Fla.) Tumor hypoxia compromises the therapeutic efficiency of photodynamic therapy (PDT) as the local oxygen concentration plays an important role in the generation of cytotoxic singlet oxygen ( O ). Herein, a versatile mesoporous nanoenzyme (NE) derived from metal-organic frameworks (MOFs) is presented for in situ generation of endogenous O to enhance the PDT efficacy under bioimaging guidance. The mesoporous NE is constructed by first coating a manganese-based MOFs with mesoporous silica, followed by a facile annealing process under the ambient atmosphere. After removing the mesoporous silica shell and post-modifying with polydopamine and poly(ethylene glycol) for improving the biocompatibility, the obtained mesoporous NE is loaded with chlorin e6 (Ce6), a commonly used photosensitizer in PDT, with a high loading capacity. Upon the O generation through the catalytic reaction between the catalytic amount NE and the endogenous H O , the hypoxic tumor microenvironment is relieved. Thus, Ce6-loaded NE serves as a H O -activated oxygen supplier to increase the local O concentration for significantly enhanced antitumor PDT efficacy in vitro and in vivo. In addition, the NE also shows T -weighted magnetic resonance imaging ability for its in vivo tracking. This work presents an interesting biomedical use of MOF-derived mesoporous NE as a multifunctional theranostic agent in cancer therapy. 10.1002/adma.201901893
    Bioconjugated Manganese Dioxide Nanoparticles Enhance Chemotherapy Response by Priming Tumor-Associated Macrophages toward M1-like Phenotype and Attenuating Tumor Hypoxia. Song Manli,Liu Ting,Shi Changrong,Zhang Xiangzhong,Chen Xiaoyuan ACS nano Hypoxia promotes not only the invasiveness of tumor cells, but also chemoresistance in cancer. Tumor associated macrophages (TAMs) residing at the site of hypoxic region of tumors have been known to cooperate with tumor cells, and promote proliferation and chemoresistance. Therefore, there is an urgent need for new strategies to alleviate tumor hypoxia and enhance chemotherapy response in solid tumors. Herein, we have taken advantage of high accumulation of TAMs in hypoxic regions of tumor and high reactivity of manganese dioxide nanoparticles (MnO2 NPs) toward hydrogen peroxide (H2O2) for the simultaneous production of O2 and regulation of pH to effectively alleviate tumor hypoxia by targeted delivery of MnO2 NPs to the hypoxic area. Furthermore, we also utilized the ability of hyaluronic acid (HA) modification in reprogramming anti-inflammatory, pro-tumoral M2 TAMs to pro-inflammatory, antitumor M1 macrophages to further enhance the ability of MnO2 NPs to lessen tumor hypoxia and modulate chemoresistance. The HA-coated, mannan-conjugated MnO2 particle (Man-HA-MnO2) treatment significantly increased tumor oxygenation and down-regulated hypoxia-inducible factor-1 α (HIF-1α) and vascular endothelial growth factor (VEGF) in the tumor. Combination treatment of the tumors with Man-HA-MnO2 NPs and doxorubicin significantly increased apparent diffusion coefficient (ADC) values of breast tumor, inhibited tumor growth and tumor cell proliferation as compared with chemotherapy alone. In addition, the reaction of Man-HA-MnO2 NPs toward endogenous H2O2 highly enhanced T1- and T2-MRI performance for tumor imaging and detection. 10.1021/acsnano.5b06779
    Erythrocyte-Membrane-Enveloped Perfluorocarbon as Nanoscale Artificial Red Blood Cells to Relieve Tumor Hypoxia and Enhance Cancer Radiotherapy. Gao Min,Liang Chao,Song Xuejiao,Chen Qian,Jin Qiutong,Wang Chao,Liu Zhuang Advanced materials (Deerfield Beach, Fla.) Hypoxia, a common feature within many types of solid tumors, is known to be closely associated with limited efficacy for cancer therapies, including radiotherapy (RT) in which oxygen is essential to promote radiation-induced cell damage. Here, an artificial nanoscale red-blood-cell system is designed by encapsulating perfluorocarbon (PFC), a commonly used artificial blood substitute, within biocompatible poly(d,l-lactide-co-glycolide) (PLGA), obtaining PFC@PLGA nanoparticles, which are further coated with a red-blood-cell membrane (RBCM). The developed PFC@PLGA-RBCM nanoparticles with the PFC core show rather efficient loading of oxygen, as well as greatly prolonged blood circulation time owing to the coating of RBCM. With significantly improved extravascular diffusion within the tumor mass, owing to their much smaller nanoscale sizes compared to native RBCs with micrometer sizes, PFC@PLGA-RBCM nanoparticles are able to effectively deliver oxygen into tumors after intravenous injection, leading to greatly relieved tumor hypoxia and thus remarkably enhanced treatment efficacy during RT. This work thus presents a unique type of nanoscale RBC mimic for efficient oxygen delivery into solid tumors, favorable for cancer treatment by RT, and potentially other types of therapy as well. 10.1002/adma.201701429