Hypoxia-triggered single molecule probe for high-contrast NIR II/PA tumor imaging and robust photothermal therapy

Hypoxia is a common characteristic of solid tumors. This important feature is associated with resistance to radio-chemotherapy, which results in poor prognosis and probability of tumor recurrence. Taking advantage of background-free NIR II fluorescence imaging and deeper-penetrating photoacoustic (PA) imaging, we developed a hypoxia-triggered and nitroreductase (NTR) enzyme-responsive single molecule probe for high-contrast NIR II/PA tumor imaging and hypoxia-activated photothermal therapy (PTT), which will overcome cellular resistance during hypoxia. Methods: The single molecule probe IR1048-MZ was synthesized by conjugating a nitro imidazole group as a specific hypoxia trigger with an IR-1048 dye as a NIR II/PA signal reporter. We investigated the NIR II fluorescence, NIR absorbance and photothermal effect in different hypoxia conditions in vitro, and performed NIR II/PA tumor imaging and hypoxia-activated photothermal therapy in mice. Results: This versatile molecular probe IR1048-MZ not only realized high-contrast tumor visualization with a clear boundary by NIR II fluorescence imaging, but also afforded deep-tissue penetration at the centimeter level by 3D PA imaging. Moreover, after being activated by NTR that is overexpressed in hypoxic tumors, the probe exhibited a significant photothermal effect for curative tumor ablation with no recurrence. Conclusions: We have developed the first hypoxia-triggered and NTR enzyme-responsive single molecule probe for high-contrast NIR II/PA tumor imaging and hypoxia-activated photothermal therapy. By tracing the activity of NTR, IR1048-MZ may be a promising contrast agent and theranostic formulation for other hypoxia-related diseases (such as cancer, inflammation, stroke, and cardiac ischemia).

[1]  Yuyan Jiang,et al.  Molecular Fluorescence and Photoacoustic Imaging in the Second Near‐Infrared Optical Window Using Organic Contrast Agents , 2018, Advanced biosystems.

[2]  Xu Zhen,et al.  Dual‐Peak Absorbing Semiconducting Copolymer Nanoparticles for First and Second Near‐Infrared Window Photothermal Therapy: A Comparative Study , 2018, Advanced materials.

[3]  L. Dobrucki,et al.  A bioreducible N-oxide-based probe for photoacoustic imaging of hypoxia , 2017, Nature Communications.

[4]  Jun Feng Zhang,et al.  Hypoxia imaging in cells and tumor tissues using a highly selective fluorescent nitroreductase probe , 2017, Scientific Reports.

[5]  Jong Seung Kim,et al.  A Mitochondria-Targeted Cryptocyanine-Based Photothermogenic Photosensitizer. , 2017, Journal of the American Chemical Society.

[6]  Paul Kumar Upputuri,et al.  Broadband Absorbing Semiconducting Polymer Nanoparticles for Photoacoustic Imaging in Second Near-Infrared Window. , 2017, Nano letters.

[7]  Baorui Liu,et al.  Successively activatable ultrasensitive probe for imaging tumour acidity and hypoxia , 2017, Nature Biomedical Engineering.

[8]  Jianping Zhou,et al.  Tumor-Penetrating Nanoparticles for Enhanced Anticancer Activity of Combined Photodynamic and Hypoxia-Activated Therapy. , 2017, ACS nano.

[9]  Hongjie Dai,et al.  Near-infrared fluorophores for biomedical imaging , 2017, Nature Biomedical Engineering.

[10]  E. Hammond,et al.  CYP450 Enzymes Effect Oxygen-Dependent Reduction of Azide-Based Fluorogenic Dyes , 2016, ACS central science.

[11]  Miao Yu,et al.  Multimodal Imaging-Guided Antitumor Photothermal Therapy and Drug Delivery Using Bismuth Selenide Spherical Sponge. , 2016, ACS nano.

[12]  Yanmin Zhang,et al.  Mitochondrial Nitroreductase Activity Enables Selective Imaging and Therapeutic Targeting. , 2016, Journal of the American Chemical Society.

[13]  Min Qian,et al.  Photothermal combined gene therapy achieved by polyethyleneimine-grafted oxidized mesoporous carbon nanospheres. , 2016, Biomaterials.

[14]  Bram Boeckx,et al.  Tumor hypoxia causes DNA hypermethylation by reducing TET activity , 2016, Nature.

[15]  Qianjun He,et al.  X-ray Radiation-Controlled NO-Release for On-Demand Depth-Independent Hypoxic Radiosensitization. , 2015, Angewandte Chemie.

[16]  H. Dai,et al.  Carbon Nanomaterials for Biological Imaging and Nanomedicinal Therapy. , 2015, Chemical reviews.

[17]  Wei Feng,et al.  Ultrasensitive near-infrared fluorescence-enhanced probe for in vivo nitroreductase imaging. , 2015, Journal of the American Chemical Society.

[18]  Shijun Shao,et al.  A rapid response "Turn-On" fluorescent probe for nitroreductase detection and its application in hypoxic tumor cell imaging. , 2015, The Analyst.

[19]  Baorui Liu,et al.  Hypoxia-specific ultrasensitive detection of tumours and cancer cells in vivo , 2015, Nature Communications.

[20]  Y. Liu,et al.  Ultrasensitive nanosensors based on upconversion nanoparticles for selective hypoxia imaging in vivo upon near-infrared excitation. , 2014, Journal of the American Chemical Society.

[21]  Shuo Diao,et al.  Ultrafast fluorescence imaging in vivo with conjugated polymer fluorophores in the second near-infrared window , 2014, Nature Communications.

[22]  Wei Lu,et al.  Combinatorial Photothermal and Immuno Cancer Therapy Using Chitosan-Coated Hollow Copper Sulfide Nanoparticles , 2014, ACS nano.

[23]  Shuo Diao,et al.  Near-Infrared II Fluorescence for Imaging Hindlimb Vessel Regeneration With Dynamic Tissue Perfusion Measurement , 2014, Circulation. Cardiovascular imaging.

[24]  K. Morokuma,et al.  Development of azo-based fluorescent probes to detect different levels of hypoxia. , 2013, Angewandte Chemie.

[25]  Shuo Diao,et al.  Biological imaging using nanoparticles of small organic molecules with fluorescence emission at wavelengths longer than 1000 nm. , 2013, Angewandte Chemie.

[26]  Nicole M. Iverson,et al.  In Vivo Biosensing Via Tissue Localizable Near Infrared Fluorescent Single Walled Carbon Nanotubes , 2013, Nature nanotechnology.

[27]  Yufang Xu,et al.  A highly sensitive long-wavelength fluorescence probe for nitroreductase and hypoxia: selective detection and quantification. , 2013, Chemical communications.

[28]  Zhe Wang,et al.  Single Continuous Wave Laser Induced Photodynamic/Plasmonic Photothermal Therapy Using Photosensitizer‐Functionalized Gold Nanostars , 2013, Advanced materials.

[29]  B. Tang,et al.  High selectivity imaging of nitroreductase using a near-infrared fluorescence probe in hypoxic tumor. , 2013, Chemical communications.

[30]  K. Hanaoka,et al.  Reversible off-on fluorescence probe for hypoxia and imaging of hypoxia-normoxia cycles in live cells. , 2012, Journal of the American Chemical Society.

[31]  H. Dai,et al.  Multifunctional in vivo vascular imaging using near-infrared II fluorescence , 2012, Nature Medicine.

[32]  Sanghwa Jeong,et al.  Imaging Depths of Near-Infrared Quantum Dots in First and Second Optical Windows , 2012, Molecular imaging.

[33]  M. Aghi,et al.  Hypoxia-induced tumor cell autophagy mediates resistance to anti-angiogenic therapy , 2012, Autophagy.

[34]  H. Nagasawa,et al.  2-Nitroimidazole-tricarbocyanine conjugate as a near-infrared fluorescent probe for in vivo imaging of tumor hypoxia. , 2012, Bioconjugate chemistry.

[35]  M. Melancon,et al.  Cancer theranostics with near-infrared light-activatable multimodal nanoparticles. , 2011, Accounts of chemical research.

[36]  Lin Zhang,et al.  Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells , 2011, Nature.

[37]  W. Wilson,et al.  Targeting hypoxia in cancer therapy , 2011, Nature Reviews Cancer.

[38]  Kevin Welsher,et al.  Deep-tissue anatomical imaging of mice using carbon nanotube fluorophores in the second near-infrared window , 2011, Proceedings of the National Academy of Sciences.

[39]  Yufang Xu,et al.  A new prodrug-derived ratiometric fluorescent probe for hypoxia: high selectivity of nitroreductase and imaging in tumor cell. , 2011, Organic letters.

[40]  Tetsuo Nagano,et al.  Hypoxia-sensitive fluorescent probes for in vivo real-time fluorescence imaging of acute ischemia. , 2010, Journal of the American Chemical Society.

[41]  G. Berchem,et al.  Role of hypoxia induced autophagy in the resistance of tumor cells to CTL-mediated specific lysis. (95.11) , 2010, The Journal of Immunology.

[42]  Naomi J Halas,et al.  Nanoshell-enabled photothermal cancer therapy: impending clinical impact. , 2008, Accounts of chemical research.

[43]  Yufang Xu,et al.  Novel nitroheterocyclic hypoxic markers for solid tumor: synthesis and biological evaluation. , 2008, Bioorganic & medicinal chemistry.

[44]  M. Hiraoka,et al.  Emission under Hypoxia: One‐Electron Reduction and Fluorescence Characteristics of an Indolequinone–Coumarin Conjugate , 2008, Chembiochem : a European journal of chemical biology.

[45]  Yufang Xu,et al.  Versatile Nitro-Fluorophore as Highly Effective Sensor for Hypoxic Tumor Cells: Design, Imaging and Evaluation , 2008, Journal of Fluorescence.

[46]  A. Bhunia,et al.  Hypoxia and chronic lung disease , 2007, Journal of Molecular Medicine.

[47]  J. Pouysségur,et al.  Hypoxia and cancer , 2007, Journal of Molecular Medicine.

[48]  C. Taylor,et al.  Hypoxia and gastrointestinal disease , 2007, Journal of Molecular Medicine.

[49]  R. Shohet,et al.  Keeping the engine primed: HIF factors as key regulators of cardiac metabolism and angiogenesis during ischemia , 2007, Journal of Molecular Medicine.

[50]  M. Hoepfner,et al.  Microscale Heat Transfer Transduced by Surface Plasmon Resonant Gold Nanoparticles. , 2007, The journal of physical chemistry. C, Nanomaterials and interfaces.

[51]  J. Pouysségur,et al.  Hypoxia signalling in cancer and approaches to enforce tumour regression , 2006, Nature.

[52]  A. N. Bashkatov,et al.  Optical properties of human skin, subcutaneous and mucous tissues in the wavelength range from 400 to 2000 nm , 2005 .

[53]  R. Jain.  Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy , 2005, Science.

[54]  D. P. O'Neal,et al.  Photo-thermal tumor ablation in mice using near infrared-absorbing nanoparticles. , 2004, Cancer letters.

[55]  J. Brown,et al.  Exploiting tumour hypoxia in cancer treatment , 2004, Nature Reviews Cancer.

[56]  G. Semenza.  Intratumoral hypoxia, radiation resistance, and HIF-1. , 2004, Cancer cell.

[57]  P. Prosposito,et al.  Fluorescence efficiency of four infrared polymethine dyes , 2003 .

[58]  S. McKeown,et al.  AQ4N: a new approach to hypoxia-activated cancer chemotherapy , 2000, British Journal of Cancer.

[59]  G. Arteel,et al.  Comparisons among pimonidazole binding, oxygen electrode measurements, and radiation response in C3H mouse tumors. , 1999, Radiation research.

[60]  A S Kennedy,et al.  Pimonidazole: a novel hypoxia marker for complementary study of tumor hypoxia and cell proliferation in cervical carcinoma. , 1998, Gynecologic oncology.

[61]  R. Koder,et al.  Steady-state kinetic mechanism, stereospecificity, substrate and inhibitor specificity of Enterobacter cloacae nitroreductase. , 1998, Biochimica et biophysica acta.

[62]  G. Wilson,et al.  Fluorescent markers for hypoxic cells: a study of nitroaromatic compounds, with fluorescent heterocyclic side chains, that undergo bioreductive binding. , 1991, Journal of medicinal chemistry.

[63]  A. Begg,et al.  Fluorescent markers of hypoxic cells: a comparison of two compounds on three cell lines. , 1985, The British journal of radiology.

[64]  E. Clarke,et al.  Nitroaryl compounds as potential fluorescent probes for hypoxia. I. Chemical criteria and constraints. , 1984, International journal of radiation oncology, biology, physics.

[65]  E. Clarke,et al.  Nitroaryl compounds as potential fluorescent probes for hypoxia. II. Identification and properties of reductive metabolites. , 1984, International journal of radiation oncology, biology, physics.

[66]  P. Prosposito,et al.  IR-Luminescent Molecules in Hybrid Materials , 2003 .