Pharmacokinetic-Modifying Linker Design Modulates Performance of Multivalent PSMA/GRPR-Cell-Targeting 177Lu Radiopharmaceuticals
12 affiliations
- 1Department of Chemistry, University of Missouri, Columbia, MO 65211, USA
- 2Research Division, Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
- 3Molecular Imaging and Theranostics Center, University of Missouri, Columbia, MO 65211, USA
- 4Radioactive Isotopes and Generator Department, Hot Labs Center, Egyptiona Atomic Energy Authority, Cairo 13759, Egypt
- 5Molecular Interactions Core, University of Missouri, Columbia, MO 65211, USA
- 6Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, School of Medicine, University of Missouri, Columbia, MO 65212, USA
- 7Cell and Immunobiology Core, University of Missouri, Columbia, MO 65211, USA
- 8Department of Radiology and Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook, NY 11794, USA
- 9Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA
- 10University of Missouri Research Reactor, University of Missouri, Columbia, MO 65211, USA
- 11Department of Radiology, School of Medicine, University of Missouri, Columbia, MO 65212, USA
- 12Ellis Fischel Cancer Center, School of Medicine, University of Missouri, Columbia, MO 65212, USA
Abstract
Background/Objectives: A series of PSMA/GRPR-targeting compounds were selected based on modifications to their respective pharmacokinetic-modifying linking groups and the structure of the PSMA-binding moiety, to examine how these alterations impact binding affinity and specificity for preclinical prostate cancer models. Methods: The multi-receptor targeting heterodimers PSMA/2PSMA-X-DOTA-Y-BBN (where X is 6-aminohexanoic acid (6AHX) or polyethylene glycol-4 (PEG4) and Y is either 8-aminooctanoic acid (8AOC) or carboxy piperidine (CP)) were radiolabeled with the theranostic isotope [177Lu]Lu. Each heterodimer construct was evaluated through characterization, stability, whole-cell in vitro studies, biodistribution in tumor-bearing mice, and in vivo small animal SPECT/CT molecular imaging. Results: In vitro evaluation of 2PSMA-6AHX-DOTA-8AOC-BBN demonstrated moderate IC50 values of 200 ± 20 nM in LNCaP cells and 21 ± 1 nM in PC3 cells. Subsequent biodistribution studies demonstrated selective tumor uptake at 4 h post-intravenous injection with uptake of 9.52 ± 2.59%ID/g in GRPR[+] PC3 tumors and 6.37 ± 0.64%ID/g in PSMA[+] PC3-PIP tumors. At 24 h post-injection, high tumor-to-blood ratios (874.0 ± 276 in PC3 and 344.3 ± 85 in PC3-PIP) and tumor-to-muscle ratios (739.8 ± 277 in PC3 and 403.5 ± 66 in PC3-PIP) were observed, further supporting the theranostic feasibility of the radiolabeled heterodimer. Small animal SPECT/CT imaging confirmed tumor targeting specificity of the heterobivalent peptide. Conclusions: Evaluation in PSMA/GRPR-expressing tumor models identified 2PSMA-6AHX-DOTA-8AOC-BBN as a leading candidate, having enhanced tumor uptake and favorable pharmacokinetics in tumor-bearing mice. These investigations advance structure–activity relationship understanding and support heterobivalent radiopharmaceuticals for precision imaging and targeted prostate cancer therapy.
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BibTeX
@article{chambers2026pharmacokineticmodifying,
title = {{Pharmacokinetic-Modifying Linker Design Modulates Performance of Multivalent PSMA/GRPR-Cell-Targeting 177Lu Radiopharmaceuticals}},
author = {Claudia G. Chambers and Grace Liles and Anupam Mathur and Tamer M. Sakr and John M. Himmelberg and Fabio Gallazi and Lisa Watkinson and Terry Carmack and Yue Guan and Susan Rottinghaus and Yubin Miao and Christine Lovingier and Thomas Collora and Gracie Miller and Michael R. Lewis and John D. Brockman and Carolyn J. Anderson and Charles J. Smith},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18203252},
url = {https://www.mdpi.com/2072-6694/18/20/3252},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Pharmacokinetic-Modifying Linker Design Modulates Performance of Multivalent PSMA/GRPR-Cell-Targeting 177Lu Radiopharmaceuticals
AU - Claudia G. Chambers
AU - Grace Liles
AU - Anupam Mathur
AU - Tamer M. Sakr
AU - John M. Himmelberg
AU - Fabio Gallazi
AU - Lisa Watkinson
AU - Terry Carmack
AU - Yue Guan
AU - Susan Rottinghaus
AU - Yubin Miao
AU - Christine Lovingier
AU - Thomas Collora
AU - Gracie Miller
AU - Michael R. Lewis
AU - John D. Brockman
AU - Carolyn J. Anderson
AU - Charles J. Smith
PY - 2026
DA - 2026/10/01
JO - Cancers
DO - 10.3390/cancers18203252
UR - https://www.mdpi.com/2072-6694/18/20/3252
AB - Background/Objectives: A series of PSMA/GRPR-targeting compounds were selected based on modifications to their respective pharmacokinetic-modifying linking groups and the structure of the PSMA-binding moiety, to examine how these alterations impact binding affinity and specificity for preclinical prostate cancer models. Methods: The multi-receptor targeting heterodimers PSMA/2PSMA-X-DOTA-Y-BBN (where X is 6-aminohexanoic acid (6AHX) or polyethylene glycol-4 (PEG4) and Y is either 8-aminooctanoic acid (8AOC) or carboxy piperidine (CP)) were radiolabeled with the theranostic isotope [177Lu]Lu. Each heterodimer construct was evaluated through characterization, stability, whole-cell in vitro studies, biodistribution in tumor-bearing mice, and in vivo small animal SPECT/CT molecular imaging. Results: In vitro evaluation of 2PSMA-6AHX-DOTA-8AOC-BBN demonstrated moderate IC50 values of 200 ± 20 nM in LNCaP cells and 21 ± 1 nM in PC3 cells. Subsequent biodistribution studies demonstrated selective tumor uptake at 4 h post-intravenous injection with uptake of 9.52 ± 2.59%ID/g in GRPR[+] PC3 tumors and 6.37 ± 0.64%ID/g in PSMA[+] PC3-PIP tumors. At 24 h post-injection, high tumor-to-blood ratios (874.0 ± 276 in PC3 and 344.3 ± 85 in PC3-PIP) and tumor-to-muscle ratios (739.8 ± 277 in PC3 and 403.5 ± 66 in PC3-PIP) were observed, further supporting the theranostic feasibility of the radiolabeled heterodimer. Small animal SPECT/CT imaging confirmed tumor targeting specificity of the heterobivalent peptide. Conclusions: Evaluation in PSMA/GRPR-expressing tumor models identified 2PSMA-6AHX-DOTA-8AOC-BBN as a leading candidate, having enhanced tumor uptake and favorable pharmacokinetics in tumor-bearing mice. These investigations advance structure–activity relationship understanding and support heterobivalent radiopharmaceuticals for precision imaging and targeted prostate cancer therapy.
SN - 2072-6694
ER -