Detection of colorectal polyps in humans using an intravenously administered fluorescent peptide targeted against c-Met.
Burggraaf Jacobus,Kamerling Ingrid M C,Gordon Paul B,Schrier Lenneke,de Kam Marieke L,Kales Andrea J,Bendiksen Ragnar,Indrevoll Bård,Bjerke Roger M,Moestue Siver A,Yazdanfar Siavash,Langers Alexandra M J,Swaerd-Nordmo Marit,Torheim Geir,Warren Madhuri V,Morreau Hans,Voorneveld Philip W,Buckle Tessa,van Leeuwen Fijs W B,Ødegårdstuen Liv-Ingrid,Dalsgaard Grethe T,Healey Andrew,Hardwick James C H
Nature medicine
Colon cancer prevention currently relies on colonoscopy using white light to detect and remove polyps, but small and flat polyps are difficult to detect and frequently missed when using this technique. Fluorescence colonoscopy combined with a fluorescent probe specific for a polyp biomarker may improve polyp detection. Here we describe GE-137, a water-soluble probe consisting of a 26-amino acid cyclic peptide that binds the human tyrosine kinase c-Met conjugated to a fluorescent cyanine dye. Intravenous administration of GE-137 leads to its accumulation specifically in c-Met-expressing tumors in mice, and it is safe and well tolerated in humans. Fluorescence colonoscopy in patients receiving intravenous GE-137 enabled visualization of all neoplastic polyps that were visible with white light (38), as well as an additional nine polyps that were not visible with white light. This first-in-human pilot study shows that molecular imaging using an intravenous fluorescent agent specific for c-Met is feasible and safe, and that it may enable the detection of polyps missed by other techniques.
10.1038/nm.3641
Photochemical Conjugation and One-Pot Radiolabelling of Antibodies for Immuno-PET.
Patra Malay,Eichenberger Larissa S,Fischer Gregor,Holland Jason P
Angewandte Chemie (International ed. in English)
Monoclonal antibodies (mAbs), immunoglobulin fragments, and other proteins are important scaffolds in the development of radiopharmaceuticals for diagnostic immuno-positron emission tomography (immuno-PET) and targeted radioimmunotherapy (RIT). Conventional methods for radiolabelling proteins with metal ions such as Ga, Cu, Zr, and Y require multi-step procedures involving pre-purification, functionalisation with a chelate, and subsequent radiolabelling. Standard coupling chemistries are time-consuming, difficult to automate, and involve synthesis, isolation, and storage of an intermediate, new molecular entity (the conjugated mAb) whose biochemical properties can differ from those of the parent protein. To circumvent these issues, we developed a photoradiochemical approach that uses fast, chemoselective, light-induced protein modification under mild conditions with novel metal-ion-binding chelates derivatised with aryl azide (ArN ) groups. Experiments show that one-pot photochemical conjugation and radiolabelling of formulated mAbs can be achieved in <20 min.
10.1002/anie.201813287
Near-Infrared Photoimmunotherapy of Cancer.
Kobayashi Hisataka,Choyke Peter L
Accounts of chemical research
This Account is the first comprehensive review article on the newly developed, photochemistry-based cancer therapy near-infrared (NIR) photoimmunotherapy (PIT). NIR-PIT is a molecularly targeted phototherapy for cancer that is based on injecting a conjugate of a near-infrared, water-soluble, silicon-phthalocyanine derivative, IRdye700DX (IR700), and a monoclonal antibody (mAb) that targets an expressed antigen on the cancer cell surface. Subsequent local exposure to NIR light turns on this photochemical "death" switch, resulting in the rapid and highly selective immunogenic cell death (ICD) of targeted cancer cells. ICD occurs as early as 1 min after exposure to NIR light and results in irreversible morphologic changes only in target-expressing cells based on the newly discovered photoinduced ligand release reaction that induces physical changes on conjugated antibody/antigen complex resulting in functional damage on cell membrane. Meanwhile, immediately adjacent receptor-negative cells are totally unharmed. Because of its highly targeted nature, NIR-PIT carries few side effects and healing is rapid. Evaluation of the tumor microenvironment reveals that ICD induced by NIR-PIT results in rapid maturation of immature dendritic cells adjacent to dying cancer cells initiating a host anticancer immune response, resulting in repriming of polyclonal CD8T cells against various released cancer antigens, which amplifies the therapeutic effect of NIR-PIT. NIR-PIT can target and treat virtually any cell surface antigens including cancer stem cell markers, that is, CD44 and CD133. A first-in-human phase 1/2 clinical trial of NIR-PIT using cetuximab-IR700 (RM1929) targeting EGFR in inoperable recurrent head and neck cancer patients successfully concluded in 2017 and led to "fast tracking" by the FDA and a phase 3 trial ( https://clinicaltrials.gov/ct2/show/NCT03769506 ) that is currently underway in 3 countries in Asia, US/Canada, and 4 countries in EU. The next step for NIR-PIT is to further exploit the immune response. Preclinical research in animals with intact immune systems has shown that NIT-PIT targeting of immunosuppressor cells within the tumor, such as regulatory T-cells, can further enhance tumor-cell-selective systemic host-immunity leading to significant responses in distant metastatic tumors, which are not treated with light. By combining cancer-targeting NIR-PIT and immune-activating NIR-PIT or other cancer immunotherapies, NIR-PIT of a local tumor, could lead to responses in distant metastases and may also inhibit recurrences due to activation of systemic anticancer immunity and long-term immune memory without the systemic autoimmune adverse effects often associated with immune checkpoint inhibitors. Furthermore, NIR-PIT also enhances nanodrug delivery into tumors up to 24-fold superior to untreated tumors with conventional EPR effects by intensively damaging cancer cells behind tumor vessels. We conclude by describing future advances in this novel photochemical cancer therapy that are likely to further enhance the efficacy of NIR-PIT.
10.1021/acs.accounts.9b00273
A thiopyrylium salt for PET/NIR-II tumor imaging and image-guided surgery.
Molecular oncology
All tumor imaging modalities have resolution limits below which deeply situated small metastatic foci may not be identified. Moreover, incomplete lesion excision will affect the outcomes of the patients. Scintigraphy is adept in locating lesions, and second near-infrared window (NIR-II) imaging may allow precise real-time tumor delineation. To achieve complete excision of all lesions, multimodality imaging is a promising method for tumor identification and management. Here, a NIR-II thiopyrylium salt, XB1034, was first synthesized and bound to cetuximab and trans-cyclooctene (TCO) to produce XB1034-cetuximab-TCO. This probe provides excellent sensitivity and high temporal resolution NIR-II imaging in mice bearing tumors developed from human breast cancer cells MDA-MB-231. To enable PET imaging, Ga-NETA-tetrazine is subsequently injected into the mice to undergo a bio-orthogonal reaction with the preinjected XB1034-cetuximab-TCO. PET images achieved in the tumor models using the pretargeting strategy are of much higher quality than those obtained using the direct radiolabeling method. Moreover, real-time NIR-II imaging allows accurate tumor excision and sentinel lymph node mapping. In conclusion, XB1034 is a promising molecular imaging probe for tumor diagnosis and treatment.
10.1002/1878-0261.12674
Novel dual-function near-infrared II fluorescence and PET probe for tumor delineation and image-guided surgery.
Chemical science
Accurate tumor identification is essential in cancer management. Incomplete excision of tumor tissue, however, negatively affects the prognosis of the patient. To accomplish radical excision of tumor tissue, radiotracers can be used that target tumor tissue and can be detected using a gamma probe during surgery. Intraoperative fluorescence imaging could allow accurate real-time tumor delineation. Herein, a novel dual-modal imaging platform using base-catalyzed double addition of thiols into a propiolamide scaffold has been developed, allowing for the highly efficient and selective assembly of various thiol units in a protecting-group-free manner. The first small-molecule based αvβ-targeted NIR-II/PET probe was concisely generated this strategy and subsequently evaluated in mice bearing the U87MG xenograft. Excellent imaging properties such as good tumor uptake, high tumor contrast and specificity, tumor delineation and image-guided surgery were achieved in the small animal models. These attractive results of allow it to be a promising αvβ-targeted NIR-II/PET probe for clinical translation.
10.1039/c7sc04774f
Hierarchically Nanostructured Hybrid Platform for Tumor Delineation and Image-Guided Surgery via NIR-II Fluorescence and PET Bimodal Imaging.
Zhang Qing,Zhou Huijun,Chen Hao,Zhang Xiao,He Shuqing,Ma Lina,Qu Chunrong,Fang Wei,Han Yanjiang,Wang Da,Huang Yuanjian,Sun Yueming,Fan Quli,Chen Yue,Cheng Zhen
Small (Weinheim an der Bergstrasse, Germany)
Bimodal imaging with fluorescence in the second near infrared window (NIR-II) and positron emission tomography (PET) has important significance for tumor diagnosis and management because of complementary advantages. It remains challenging to develop NIR-II/PET bimodal probes with high fluorescent brightness. Herein, bioinspired nanomaterials (melanin dot, mesoporous silica nanoparticle, and supported lipid bilayer), NIR-II dye CH-4T, and PET radionuclide Cu are integrated into a hybrid NIR-II/PET bimodal nanoprobe. The resultant nanoprobe exhibits attractive properties such as highly uniform tunable size, effective payload encapsulation, high stability, dispersibility, and biocompatibility. Interestingly, the incorporation of CH-4T into the nanoparticle leads to 4.27-fold fluorescence enhancement, resulting in brighter NIR-II imaging for phantoms in vitro and in situ. Benefiting from the fluorescence enhancement, NIR-II imaging with the nanoprobe is carried out to precisely delineate and resect tumors. Additionally, the nanoprobe is successfully applied in tumor PET imaging, showing the accumulation of the nanoprobe in a tumor with a clear contrast from 2 to 24 h postinjection. Overall, this hierarchically nanostructured platform is able to dramatically enhance fluorescent brightness of NIR-II dye, detect tumors with NIR-II/PET imaging, and guide intraoperative resection. The NIR-II/PET bimodal nanoprobe has high potential for sensitive preoperative tumor diagnosis and precise intraoperative image-guided surgery.
10.1002/smll.201903382
Biomineralized Gd O @HSA Nanoparticles as a Versatile Platform for Dual-Modal Imaging and Chemo-Phototherapy-Synergized Tumor Ablation.
Hao Tangna,Chen Qixian,Qi Yan,Sun Pengyuan,Chen Dawei,Jiang Weiwei,Liu Kexin,Sun Huijun,Li Lei,Ding Jianxun,Li Zhen
Advanced healthcare materials
A great challenge still remains to explore the facile approaches to construct multifunctional nanoparticles for acquiring precise cancer theranostics. Herein, a biocompatible theranostic nanoplatform capable of simultaneous cancer imaging and therapy is attempted by loading of paclitaxel (PTX) and indocyanine green (ICG) molecules into the matrix of Gd O @human serum albumin (HSA) nanoparticles (PIGH NPs) via hydrophobic interaction. The subsequent in vitro investigations reveal that the PIGH NPs afford uniform particle size, sustained drug release profile, strong longitudinal relaxivity, potent photothermal effect, effective singlet oxygen generation, and ideal resistance to photobleaching. Moreover, the PIGH NPs achieve high cellular uptake, efficient cytoplasmic drug translocation based on singlet oxygen-triggered endolysosomal disruption and prominent cytotoxicity effect against 4T1 cells under 808 nm near-infrared (NIR) irradiation in contrast to PTX/ICG-loaded HSA nanoparticles (PIH NPs) and free PTX/ICG. After intravenous injection, the PIGH NPs exhibit preferable tumor accumulation and achieve effective tumor ablation in 4T1 tumor bearing mouse model with excellent dual near-infrared fluorescence/magnetic resonance (NIRF/MR) imaging guided synergistic chemo-phototherapy. Hence, the PIGH NPs can be utilized as potential theranostic nanosystem for simultaneous cancer imaging and therapy.
10.1002/adhm.201901005