Evaluation of Nonpeptidic Ligand Conjugates for SPECT Imaging of Hypoxic and Carbonic Anhydrase IX-Expressing Cancers

• Published in: Bioconjugate chemistry Vol. 27; no. 7; pp. 1762 - 1769
• Main Authors: Lv, Peng-Cheng, Putt, Karson S, Low, Philip S
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.07.2016; Amer Chemical Soc
• Subjects: Animals; Binding sites; Biochemical Research Methods; Biochemistry & Molecular Biology; Biomarkers; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - metabolism; Carbonic Anhydrase Inhibitors - pharmacokinetics; Carbonic Anhydrase IX - antagonists & inhibitors; Carbonic Anhydrase IX - metabolism; Cell Transformation, Neoplastic; Chemistry; Chemistry, Multidisciplinary; Chemistry, Organic; Chemotherapy; Gene expression; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Hypoxia; Life Sciences & Biomedicine; Ligands; Male; Mice; Nuclear medicine; Oncology; Physical Sciences; Polyethylene Glycols - chemistry; Rhodamines - chemistry; Science & Technology; Technetium - chemistry; Tissue Distribution; Tomography, Emission-Computed, Single-Photon - methods; Tumor Hypoxia; CA-IX; LUNG-CANCER; POSITRON-EMISSION-TOMOGRAPHY; PRIMARY CERVICAL-CANCER; CARBONIC-ANHYDRASE-9 EXPRESSION; POOR-PROGNOSIS; IN-VIVO; BIOLOGICAL EVALUATION; MONOCLONAL-ANTIBODY; RENAL-CELL CARCINOMA
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/acs.bioconjchem.6b00271

As tumors grow, vasculature is often deficient or malformed, resulting in many localized areas of hypoxia. Cells located in these hypoxic regions exhibit an altered gene expression pattern that can significantly alter resistance to conventional anticancer treatments such as ionizing radiation and chemotherapeutic drugs. A priori knowledge of the level of hypoxia within a tumor may better guide clinical care. In an effort to create a hypoxia specific imaging agent, a ligand for the tissue hypoxia marker, carbonic anhydrase IX (CA IX), was synthesized and used as a targeting ligand to deliver an attached 99mTc-chelating agent. Binding of the resulting conjugates to hypoxic cancer cells was first characterized in vitro. Whole animal imaging and biodistribution studies then were performed to determine tumor specificity in vivo. Several conjugates were found to bind selectively to CA IX expressing tumors in a receptor-dependent manner. We suggest that such conjugates could prove useful in identifying hypoxic cancers and/or quantitating the level of hypoxia within a tumor.