Journal article
Structural modifications toward improved lead-203/lead-212 peptide-based image-guided alpha-particle radiopharmaceutical therapies for neuroendocrine tumors
European journal of nuclear medicine and molecular imaging, Vol.51(4), pp.1147-1162
03/2024
DOI: 10.1007/s00259-023-06494-9
PMCID: PMC10881741
PMID: 37955792
Abstract
PURPOSE The lead-203 (203Pb)/lead-212 (212Pb) elementally identical radionuclide pair has gained significant interest in the field of image-guided targeted alpha-particle therapy for cancer. Emerging evidence suggests that 212Pb-labeled peptide-based radiopharmaceuticals targeting somatostatin receptor subtype 2 (SSTR2) may provide improved effectiveness compared to beta-particle-based therapies for neuroendocrine tumors (NETs). This study aims to improve the performance of SSTR2-targeted radionuclide imaging and therapy through structural modifications to Tyr3-octreotide (TOC)-based radiopharmaceuticals .METHODS New SSTR2-targeted peptides were designed and synthesized with the goal of optimizing the incorporation of Pb isotopes through the use of a modified cyclization technique; the introduction of a Pb-specific chelator (PSC); and the insertion of polyethylene glycol (PEG) linkers. The binding affinity of the peptides and the cellular uptake of 203Pb-labeled peptides were evaluated using pancreatic AR42J (SSTR2+) tumor cells and the biodistribution and imaging of the 203Pb-labeled peptides were assessed in an AR42J tumor xenograft mouse model. A lead peptide was identified (i.e., PSC-PEG2-TOC), which was then further evaluated for efficacy in 212Pb therapy studies. RESULTS The lead radiopeptide drug conjugate (RPDC) - [203Pb]Pb-PSC-PEG2-TOC - significantly improved the tumor-targeting properties, including receptor binding and tumor accumulation and retention as compared to [203Pb]Pb-DOTA0-Tyr3-octreotide (DOTATOC). Additionally, the modified RPDC exhibited faster renal clearance than the DOTATOC counterpart. These advantageous characteristics of [212Pb]Pb-PSC-PEG2-TOC resulted in a dose-dependent therapeutic effect with minimal signs of toxicity in the AR42J xenograft model. Fractionated administrations of 3.7 MBq [212Pb]Pb-PSC-PEG2-TOC over three doses further improved anti-tumor effectiveness, resulting in 80% survival (70% complete response) over 120 days in the mouse model .CONCLUSION Structural modifications to chelator and linker compositions improved tumor targeting and pharmacokinetics (PK) of 203/212Pb peptide-based radiopharmaceuticals for NET theranostics. These findings suggest that PSC-PEG2-TOC is a promising candidate for Pb-based targeted radionuclide therapy for NETs and other types of cancers that express SSTR2.
Details
- Title: Subtitle
- Structural modifications toward improved lead-203/lead-212 peptide-based image-guided alpha-particle radiopharmaceutical therapies for neuroendocrine tumors
- Creators
- Dongyoul Lee - Korea Military AcademyMengshi LiDijie LiuNicholas J BaumhoverEdwin A SagastumeBrenna M MarksPrerna Rastogi - University of IowaF Christopher Pigge - University of IowaYusuf Menda - University of IowaFrances L JohnsonMichael K Schultz - University of Iowa
- Resource Type
- Journal article
- Publication Details
- European journal of nuclear medicine and molecular imaging, Vol.51(4), pp.1147-1162
- DOI
- 10.1007/s00259-023-06494-9
- PMID
- 37955792
- PMCID
- PMC10881741
- NLM abbreviation
- Eur J Nucl Med Mol Imaging
- ISSN
- 1619-7070
- eISSN
- 1619-7089
- Grant note
- name: National Institute of Health, award: R44CA268314, R44CA254613, 1R01CA243014, 1P50CA174521; DOI: 10.13039/100000056, name: National Institute of Nursing Research, award: R44CA250872
- Language
- English
- Electronic publication date
- 11/13/2023
- Date published
- 03/2024
- Academic Unit
- Radiology; Stead Family Department of Pediatrics; Pathology; Radiation Oncology; Chemistry; Internal Medicine
- Record Identifier
- 9984512058702771
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