Development of a Novel HER2-Targeted Peptide Probe for Dual-Modal Imaging of Tumors

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Abstract

Human epidermal growth factor receptor 2 (HER2) may serve as a valid target for diagnosis of cancer. The probes with capability for near-infrared window one region II (NIR-II) and positron emission tomography (PET) dual-modal imaging are highly desired for HER2-positive tumor detection. Herein, three HER2-targeted peptides were designed and further modified with indocyanine green (ICG) and 2,2',2″,2″-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA), which were used for NIR-II imaging and complexation with 68Ga for PET. Among the resulted probes (DOTA-ZC01-ICG, DOTA-KSP-ICG, and DOTA-ZC02-ICG), NIR-II imaging revealed that DOTA-ZC02-ICG had the best tumor imaging performance in SKOV3 tumor-bearing mice. The highest T/N ratio (5.4) was achieved at 4 h post-injection. Furthermore, DOTA-ZC02-ICG was radiolabeled with 68Ga to generate [68Ga]-DOTA-ZC02-ICG for PET, and it clearly delineated at 0.5, 1, and 2 h post-injection. The tumor uptake reached 1.9 %ID/g at 0.5 h, and the tumor uptakes were significantly inhibited in the blocking study (p < 0.05). Overall, it provides a promising technique for tumor dual-modal imaging and a new molecular scaffold for developing HER2-targeted theranostic agents.

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High performance plasma amyloid-β biomarkers for Alzheimer’s disease

Akinori Nakamura, NAOKI KANEKO, Victor Villemagne … (2018)

To facilitate clinical trials of disease-modifying therapies for Alzheimer's disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-β deposition in the brain-the earliest pathological signature of Alzheimer's disease-are amyloid-β positron-emission tomography (PET) imaging or measurement of amyloid-β in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-β markers. Here we demonstrate the measurement of high-performance plasma amyloid-β biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-β precursor protein (APP)669-711/amyloid-β (Aβ)1-42 and Aβ1-40/Aβ1-42 ratios, and their composites, to predict individual brain amyloid-β-positive or -negative status was determined by amyloid-β-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer's disease. All test biomarkers showed high performance when predicting brain amyloid-β burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-β-PET burden and levels of Aβ1-42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-β burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.

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HER2-targeted therapies — a role beyond breast cancer

Do-Youn Oh, Yung-Jue Bang (2019)

HER2 is an established therapeutic target in a large subset of women with breast cancer; a variety of agents including trastuzumab, pertuzumab, lapatinib, neratinib and trastuzumab emtansine (T-DM1) have been approved for the treatment of HER2-positive breast cancer. HER2 is also overexpressed in subsets of patients with other solid tumours. Notably, the addition of trastuzumab to first-line chemotherapy has improved the overall survival of patients with HER2-positive gastric cancer, and has become the standard-of-care treatment for this group of patients. However, trials involving pertuzumab, lapatinib and T-DM1 have failed to provide significant improvements in the outcomes of patients with HER2-positive gastric cancer. HER2-targeted therapies are also being tested in patients with other solid tumours harbouring HER2 overexpression, and/or amplifications or other mutations of the gene encoding HER2 (ERBB2), including biliary tract, colorectal, non-small-cell lung and bladder cancers. The experience with gastric cancer suggests that the successes observed in HER2-positive breast cancer might not be replicated in these other tumour types, owing to differences in the level of HER2 overexpression and other aspects of disease biology. In this Review, we describe the current role of HER2-targeted therapies beyond breast cancer and also highlight the potential of novel HER2-targeted agents that are currently in clinical development.

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HER2-positive breast cancer.

Sibylle Loibl, Luca Gianni (2017)

Anti-HER2 treatment for HER2-positive breast cancer has changed the natural biology of this disease. This Series article reviews the main achievements so far in the treatment of both metastatic and early HER2-positive breast cancer. The success of neoadjuvant therapy in HER2-positive early breast cancer is especially acknowledged, as pertuzumab has been approved on the basis of a higher proportion of patients achieving a pathological complete response with pertuzumab and trastuzumab than with trastuzumab alone in a neoadjuvant study. Event-free survival after the confirmatory adjuvant trial completed recruitment was numerically better with pertuzumab plus trastuzumab than with trastuzumab alone. With survival rates of almost 5 years in women with metastatic HER2-positive breast cancer and 75% of patients achieving a pathological complete response, new treatments in the past decade have clearly improved the prognosis of HER2-positive breast cancer. Despite these achievements, however, the persisting high toll of deaths resulting from HER2-positive breast cancer calls for continued, intensive clinical research of newer therapies and combinations.

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Author and article information

Contributors

Rui Cao: (View ORCID Profile)

Chaoquan Lai: (View ORCID Profile)

Hongguang Liu: (View ORCID Profile)

Zhen Cheng: (View ORCID Profile)

Journal

Title: Journal of Medicinal Chemistry

Abbreviated Title: J. Med. Chem.

Publisher: American Chemical Society (ACS)

ISSN (Print): 0022-2623

ISSN (Electronic): 1520-4804

Publication date Created: June 08 2023

Publication date (Electronic): May 29 2023

Publication date (Print): June 08 2023

Volume: 66

Issue: 11

Pages: 7523-7533

Affiliations

[1 ]Institute of Molecular Medicine, College of Life and Health Sciences, Northeastern University, Shenyang 110167, China

[2 ]State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

[3 ]Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China