Evaluation of radioiodinated protein conjugates and their potential metabolites containing lysine-urea-glutamate (LuG), PEG and closo-decaborate(2-) as models for targeting astatine-211 to metastatic prostate cancer
| Autor: | Robert L. Vessella, Ming-Kuan Chyan, D. Scott Wilbur, Holly M. Nguyen, Yawen Li, Donald K. Hamlin |
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| Rok vydání: | 2020 |
| Předmět: |
Streptavidin
Male Cancer Research Metabolite Lysine Article 030218 nuclear medicine & medical imaging Polyethylene Glycols 03 medical and health sciences Succinylation chemistry.chemical_compound Mice 0302 clinical medicine PEG ratio Borates medicine Animals Humans Radiology Nuclear Medicine and imaging Tissue Distribution Neoplasm Metastasis Prostatic Neoplasms Human serum albumin Cell Transformation Neoplastic Biochemistry chemistry 030220 oncology & carcinogenesis Molecular Medicine Linker Astatine Oligopeptides Conjugate medicine.drug |
| Zdroj: | Nucl Med Biol |
| ISSN: | 1872-9614 |
| Popis: | Introduction The use of lysine-urea-glutamate (LuG) for targeting the PSMA antigen on prostate cancer (PCa) is a promising method for delivering the alpha particle-emitting radionuclide astatine-211 (211At) to metastatic PCa. High kidney localization has been a problem with radiolabeled LuG derivatives, but has been adequately addressed in radiometal-labeled DOTA-LuG derivatives by linker optimization. Herein, we report an investigation of an alternate approach to diminishing the kidney concentrations of radiolabeled LuG-containing compounds. Methods Our approach involves PEGylated LuG moieties and closo-decaborate (2-) moieties conjugated to streptavidin (SAv) or human serum albumin (HSA). After preparing the LuG conjugates, SAv and HSA conjugates were succinylated to decrease their kidney localization and radioiodinated for evaluation in athymic mice bearing C4-2B osseous PCa tumor xenografts. Results Covalently attaching LuG to succinylated SAv and HSA significantly reduced kidney localization, but unfortunately succinylation resulted in decreased tumor concentrations. In contrast, a potential metabolite [131I]16b, an unconjugated LuG derivative containing a dPEG4® linker, provided tumor concentrations of ~15% ID/g at 4 h pi. A second unconjugated LuG derivative with a similar structure, but containing a dPEG12® linker, [131I]16a had tumor concentrations of ~4%ID/g at 4 h pi. Those results suggest that long PEG linkers also affect tumor localization in a negative manner. Conclusion Conjugation of PEGylated LuG derivatives to proteins can be an effective approach to diminishing kidney localization of radiolabeled LuG reagents, but the protein, linker and the method of linkage need to be further studied. Additionally, modification of the unconjugated 16b to decrease kidney localization may provide PCa targeting agents for use with radiohalogens, including 211At. Advances in knowledge and implications for patient care: This study is the first to evaluate PEGylated LuG and closo-decaborate (2-) moieties conjugated to proteins as potential methods for diminishing the kidney concentrations of radiolabeled LuG-containing compounds. |
| Databáze: | OpenAIRE |
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