Development of Improved Tumor-Residualizing, GRPR-Targeted Agents: Preclinical Comparison of an Endolysosomal
Wenting Zhang1,2, Wei Fan1,2, Brendan M Ottemann3
1Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska.
Abstract:
Receptor-targeted radiopharmaceuticals based on low-molecular-weight carriers offer many clinically advantageous attributes relative to macromolecules but have generally been hampered by their rapid clearance from tumors, thus diminishing tumor-to-nontarget tissue ratios. Herein, we present a strategy using irreversible inhibitors (E-64 derivative) of cysteine cathepsins (CCs) as trapping agents to increase the tumor retention of receptor-targeted agents. Methods: We incorporated these CC-trapping agents into agonistic and antagonistic pharmacophores targeting the gastrin-releasing peptide receptor (GRPR). The synthesized radioconjugates with either an incorporated CC inhibitor or a matching control were examined using in vitro and in vivo models of the GRPR-positive, PC-3 human prostate cancer cell line. Results: From the in vitro studies, multiple techniques confirmed that the CC-trapping, GRPR-targeted constructs were able to increase cellular retention by forming intracellular macromolecule adducts. In PC-3 tumor-bearing xenograft mice, the CC-trapping, GRPR-targeted agonistic and antagonistic constructs led to an approximately 2-fold increase in tumor retention with a corresponding improvement in most tumor-to-nontarget tissue ratios over 72 h. Conclusion: CC endolysosomal trapping provides a pathway to increase the efficacy and clinical potential of low-molecular-weight, receptor-targeted agents.
Insights
This study introduces cysteine cathepsin (CC) inhibitors as trapping agents to enhance tumor retention of receptor-targeted radiopharmaceuticals. This strategy improves tumor-to-nontarget tissue ratios for potential cancer therapies.
Area of Science:
- Radiopharmaceutical development
- Molecular imaging
- Cancer therapy
Background:
- Low-molecular-weight radiopharmaceuticals offer clinical advantages but suffer from rapid tumor clearance.
- Poor tumor retention diminishes tumor-to-nontarget tissue ratios, limiting clinical efficacy.
- Cysteine cathepsins (CCs) are implicated in cellular processes affecting drug retention.
Purpose of the Study:
- To develop and evaluate a strategy using CC inhibitors as trapping agents to increase tumor retention of receptor-targeted agents.
- To assess the impact of CC trapping on the efficacy of radiopharmaceuticals targeting the gastrin-releasing peptide receptor (GRPR).
Main Methods:
- Incorporation of irreversible CC inhibitors into GRPR-targeting pharmacophores (agonistic and antagonistic).
- Synthesis and characterization of radioconjugates with and without CC inhibitors.
- In vitro evaluation using PC-3 human prostate cancer cells.
- In vivo studies in PC-3 tumor-bearing xenograft mouse models.
Main Results:
- In vitro studies demonstrated increased cellular retention of CC-trapping constructs via intracellular macromolecule adduct formation.
- In vivo studies showed a ~2-fold increase in tumor retention for CC-trapping GRPR-targeted agents.
- Improved tumor-to-nontarget tissue ratios were observed over 72 hours in xenograft models.
Conclusions:
- Endolysosomal trapping via CC inhibition is a viable strategy to enhance tumor retention of low-molecular-weight radiopharmaceuticals.
- This approach holds potential for increasing the clinical efficacy of targeted cancer therapies.
- CC trapping offers a pathway to improve the therapeutic index of receptor-targeted agents.
