1. An N-Acetylgalactosamino Dendron-Clearing Agent for High-Therapeutic-Index DOTA-Hapten Pretargeted Radioimmunotherapy
- Author
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Donald B. Axworthy, Darren R. Veach, Guangbin Yang, Mitesh Patel, Hong Xu, Nai-Kong V. Cheung, Hong-fen Guo, Ouathek Ouerfelli, Sarah M. Cheal, Steven M. Larson, and Pat Zanzonico
- Subjects
Dendrimers ,Acetylgalactosamine ,Immunoconjugates ,Biomedical Engineering ,Biotin ,Pharmaceutical Science ,Bioengineering ,02 engineering and technology ,01 natural sciences ,Article ,Heterocyclic Compounds, 1-Ring ,Mice ,chemistry.chemical_compound ,Therapeutic index ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,DOTA ,Tissue Distribution ,Clearing Agent ,Pretargeted Radioimmunotherapy ,Pretargeting ,Pharmacology ,Kidney ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Radioimmunotherapy ,021001 nanoscience & nanotechnology ,Xenograft Model Antitumor Assays ,0104 chemical sciences ,medicine.anatomical_structure ,Cancer research ,Colorectal Neoplasms ,0210 nano-technology ,Haptens ,Hapten ,Biotechnology - Abstract
Clearing agents (CAs) can rapidly remove non-localized targeting biomolecules from circulation for hepatic catabolism, thereby enhancing the therapeutic index (TI), especially for blood (marrow), of the subsequently administered radioisotope in any multi-step pretargeting strategy. Herein we describe the synthesis and in vivo evaluation of a fully synthetic glycodendrimer-based CA for DOTA-based pretargeted radioimmunotherapy (DOTA-PRIT). The novel dendron-CA consists of a non-radioactive yttrium-DOTA-Bn molecule attached via a linker to a glycodendron displaying sixteen terminal α-thio-N-acetylgalactosamine (α-SGalNAc) units (CCA α-16-DOTA-Y(3+); molecular weight: 9059 Da). Pretargeting [(177)Lu]LuDOTA-Bn with CCA α-16-DOTA-Y(3+) to GPA33-expressing SW1222 human colorectal xenografts was highly effective, leading to absorbed doses of [(177)Lu]LuDOTA-Bn for blood, tumor, liver, spleen, and kidneys of 11.7, 468, 9.97, 5.49, and 13.3 cGy/MBq, respectively. Tumor-to-normal tissues absorbed-dose ratios (i.e., TIs) ranged from 40 (e.g., for blood and kidney) to about 550 for stomach.
- Published
- 2019