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Published on: January 7, 2019
Disulfide-Directed Multicylic Peptides for Targeting and Radionuclide Imaging of HER2 Expressing Tumors
Jie Zhuang1, Xueyao Chen2, Siqi Zhang2
1Department of Chemistry, College of Chemistry and Chemical Engineering, The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, Xiamen University, Xiamen 361005, China.
Abstract:
Human epidermal growth factor receptor 2 (HER2) is a critical therapeutic target in various cancers, but its accurate noninvasive quantification remains challenging. Existing positron emission tomography (PET) tracers, such as antibodies and peptides, are limited by suboptimal clearance, insufficient tumor uptake and retention, and poor proteolytic stability. Here, we introduce a new class of disulfide-directed multicyclic peptides (DDMPs) that combine a conformationally rigid and stable scaffold with excellent HER2-binding properties. Using yeast display and directed evolution, we identified optimized DDMPs with single-digit nanomolar affinity for HER2. Alanine scanning mutagenesis revealed conserved residues that were amenable to functional modification. After gallium-68 (68Ga) radiolabeling, these DDMPs demonstrated significantly enhanced tumor accumulation, prolonged retention, and superior sensitivity in detecting HER2-expressing tumors compared to those of existing peptide tracers. Our work establishes DDMPs as a structurally distinct class of peptide tracers with superior performance, representing a significant advancement toward the clinical translation of precision PET imaging for HER2-positive cancers.
Insights
New disulfide-directed multicyclic peptides (DDMPs) offer improved HER2-targeting for positron emission tomography (PET) imaging. These novel tracers show enhanced tumor uptake and retention, advancing precision oncology for HER2-positive cancers.
Area of Science:
- Biochemistry
- Molecular Biology
- Radiochemistry
Background:
- Human epidermal growth factor receptor 2 (HER2) is a key target in cancer therapy.
- Current positron emission tomography (PET) tracers for HER2 have limitations including poor stability and tumor targeting.
Purpose of the Study:
- To develop a novel class of HER2-specific PET tracers with improved properties.
- To evaluate the efficacy of disulfide-directed multicyclic peptides (DDMPs) for noninvasive HER2 quantification.
Main Methods:
- Yeast display and directed evolution were used to identify high-affinity HER2 binders.
- Disulfide-directed multicyclic peptides (DDMPs) were synthesized and radiolabeled with Gallium-68 (68Ga).
- In vivo PET imaging studies were performed to assess tumor uptake, retention, and detection sensitivity.
Main Results:
- Optimized DDMPs exhibited single-digit nanomolar affinity for HER2.
- 68Ga-labeled DDMPs showed significantly enhanced tumor accumulation and prolonged retention compared to existing peptide tracers.
- DDMPs demonstrated superior sensitivity in detecting HER2-expressing tumors.
Conclusions:
- Disulfide-directed multicyclic peptides (DDMPs) represent a novel class of PET tracers with superior performance for HER2 imaging.
- DDMPs offer a promising advancement for clinical translation in precision PET imaging of HER2-positive cancers.
