title: Near-infrared fluorescence heptamethine carbocyanine dyes mediate imaging and targeted drug delivery for human brain tumor.
abstract: Brain tumors and brain metastases are among the deadliest malignancies of all human cancers, largely due to the cellular blood-brain and blood-tumor barriers that limit the delivery of imaging and therapeutic agents from the systemic circulation to tumors. Thus, improved strategies for brain tumor visualization and targeted treatment are critically needed. Here we identified and synthesized a group of near-infrared fluorescence (NIRF) heptamethine carbocyanine dyes and derivative NIRF dye-drug conjugates for effective imaging and therapeutic targeting of brain tumors of either primary or metastatic origin in mice, which is mechanistically mediated by tumor hypoxia and organic anion-transporting polypeptide genes. We also demonstrate that these dyes, when conjugated to chemotherapeutic agents such as gemcitabine, significantly restricted the growth of both intracranial glioma xenografts and prostate tumor brain metastases and prolonged survival in mice. These results show promise in the application of NIRF dyes as novel theranostic agents for the detection and treatment of brain tumors.
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Jason Boyang
authors.initials: JB
authors.lastname: Wu
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Laboratory Animal Center, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Changhong
authors.initials: C
authors.lastname: Shi
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Gina Chia-Yi
authors.initials: GC
authors.lastname: Chu
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Qijin
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Qinlong
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Yu
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Haiyen E
authors.initials: HE
authors.lastname: Zhau
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: Leland.Chung@cshs.org.
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D002232:Carbocyanines / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D003952:Diagnostic Imaging; D016503:Drug Delivery Systems; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D000860:Hypoxia / Q000235:genetics; D008297:Male; D008819:Mice, Nude; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D027361:Organic Anion Transporters / Q000235:genetics; D011471:Prostatic Neoplasms / Q000473:pathology; D019265:Spectroscopy, Near-Infrared; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D002232:Carbocyanines; D005456:Fluorescent Dyes; D027361:Organic Anion Transporters; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Blood brain barrier; Brain tumor; Drug delivery; Heptamethine carbocyanine; Hypoxia; Near-infrared fluorescence dye