Structure-based Design of Peptides with High Affinity and Specificity to HER2 Positive Tumors

Geng, Li; Wang, Zihua; Yang, Xiaoliang; Li, Dan; Lian, Wenxi; Xiang, Zhichu; Wang, Weizhi; Bu, Xiangli; Lai, Wenjia; Hu, Zhiyuan; Fang, Qiaojun

doi:10.7150/thno.12398

Cited by 35 publications

(34 citation statements)

References 54 publications

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“…1–3 In mouse models we have shown that the efficacy for the treatment of human HER2-positive breast cancer with free trastuzumab alone could be significantly increased when the antibody was co-liganded with poly(β-Lrange-malic acid and an antisense oligonucleotide (AON) targeting HER2-mRNA. 4,5 After the successful use of trastuzumab with affinity in the low nanomolar range, 6,7 peptides with affinities in the high nanomolar region 7–9 and affibodies with affinities in the picomolar to low nanomolar regions have been developed and successfully used for tumor imaging. 10,11 Examples of targeted therapy using anti-HER2/neu peptide (AHNP) or affibodies alone or in combination with other molecules have demonstrated variable degrees of tumor-specific growth inhibition.…”

Section: Introductionmentioning

confidence: 99%

HER2-positive breast cancer targeting and treatment by a peptide-conjugated mini nanodrug

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et al. 2017

Nanomedicine: Nanotechnology, Biology and Medicine

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HER2+ breast cancer is one of the most aggressive forms of breast cancer. The new polymalic acid-based mini nanodrug copolymers are synthesized and specifically characterized to inhibit growth of HER2+ breast cancer. These mini nanodrugs are highly effective and in the clinic may substitute for trastuzumab (the marketed therapeutic antibody) and antibody targeted nanobiocongugates. Novel mini nanodrugs are designed to have slender shape and small size. HER2+ cells were recognized by the polymer-attached trastuzumab-mimetic 12-mer peptide. Synthesis of the nascent cell-transmembrane HER2/neu receptors by HER2+ cells was inhibited by antisense oligonucleotides that prevented cancer cell proliferation and significantly reduced tumor size by more than 15 times vs. untreated control or PBS-treated group. We emphasize that the shape and size of mini nanodrugs can enhance penetration of multiple bio-barriers to facilitate highly effective treatment. Replacement of trastuzumab by the mimetic peptide favors reduced production costs and technical efforts, and a negligible immune response.

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Section: Introductionmentioning

confidence: 99%

HER2-positive breast cancer targeting and treatment by a peptide-conjugated mini nanodrug

Ding

Gangalum

Galstyan

et al. 2017

Nanomedicine: Nanotechnology, Biology and Medicine

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“…The comparison revealed a certain resemblance with the Affibody at the region starting from lysine at position 27 (KRAFIRSLYDDPS vs. KAAYSLGYYNPT). In addition, this region in the Affibody molecule contains key residues for HER2 binding [15,44]. Hence, the exact interaction domain between HER2 and cP(AA)_(YY) and a possible overlapping with the Affibody binding site need to be determined by structural studies of the complex.…”

Section: Discussionmentioning

confidence: 99%

Structure–Activity Relationship of HER2 Receptor Targeting Peptide and Its Derivatives in Targeted Tumor Therapy

et al. 2020

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Human epidermal growth factor (HER2) is a transmembrane tyrosine kinase receptor that is frequently overexpressed in breast cancer. Its increased level prognoses a poor patient outcome and a high mortality rate. Despite the widening spectrum of therapies that are becoming available to treat HER2+ breast cancer, its side effects and resistance still make this protein a valuable object of research in targeted tumor therapy. The role of tumor-targeting peptides has become more and more prominent in the last few decades due to their simple synthesis and pharmakokinetic properties. Here, we examine two fluorescently-labeled HER2-specific peptides and their combined analogues that are developed to target the extracellular region of HER2. The peptides are investigated on breast cancer cell lines with different HER2 expression profiles. Moreover, their extracellular localization and specificity are confirmed by flow cytometry and confocal microscopy. Therefore, a new, combined HER2 binding conjugate is obtained that interacts with HER2-overexpressing cells with high affinity and specificity. Furthermore, secondary structure prediction reveals that the α-helical content of the peptides is associated with their receptor recognition. This highly specific conjugate can be used as a starting point for diagnostical or drug-targeting purposes in upcoming studies.Biomolecules 2020, 10, 183 2 of 17 receptors. The only exception is HER2, which does not directly bind to any known ligands [3]. HER2 can form heterodimers with all three other members of the protein family, or, in the case of an elevated receptor concentration (such as the case in cancer), it can be found as homodimers as well. The most potent heterodimer consists of HER2 and HER3, and it is considered to be the most active signaling complex among tyrosine kinase dimers. Upon ligand binding, phosphorylation occurs and activates several downstream signaling pathways: the phosphatidyl-inositol-3 kinase (PI3K) and the Ras/Raf mitogen-activated protein kinase (MAPK) pathways. Consequently, cell proliferation, cell survival and apoptosis inhibition is enhanced [4].Under normal circumstances, HER2 plays a vital role in mitogenic signaling, and the expression level of HER2 remains stable. However, when the overexpression of HER2 occurs, it can disrupt the dynamic balance of many cellular mechanisms and lead to uncontrollable tumor growth because: (i) Overexpression makes excessive HER2 receptors available to form extra heterocomplexes, (ii) HER2 may strengthen the affinity of ligand-binding for other receptors, (iii) HER2 might weaken the specificity of its heterodimerization partners, (iv) HER2-engaged dimerization can activate proliferation and survival, and (v) HER2-containing heterodimers may escape from the internalization or degradation of HER2 dimers. All these processes lead to increased tumorigenesis and metastasis [5,6].Because HER2 has a crucial role in poor breast cancer prognosis, several therapies have been developed in the last decades to target this receptor. ...

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“…In the last decade, several HER2-targeted peptides have been identified and evaluated for applications in tumor inhibition or drug delivery (37)(38)(39)(40), and some specific agents have been used in NIRF imaging (41,42). However, little research on peptide-based nuclear imaging of HER2 has been reported.…”

Section: Discussionmentioning

confidence: 99%

SPECT/CT Imaging of the Novel HER2-Targeted Peptide Probe ^99mTc-HYNIC-H6F in Breast Cancer Mouse Models

Wang

et al. 2017

J Nucl Med

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Overexpression of human epidermal growth factor receptor 2 (HER2) plays important roles in tumorigenesis and tumor progression in breast cancer. Nuclear imaging of HER2 expression in tumors might detect all HER2-positive tumors throughout the body and guide HER2-targeted therapies for patients. We therefore aimed to develop a HER2-targeted peptide probe for breast cancer imaging. A novel SPECT imaging probe, 99m Tc-HYNIC-H6F, was prepared and then evaluated in breast cancer animal models. Methods: The HER2-targeted peptide H6F (YLFFVFER) was conjugated with the bifunctional chelator hydrazinonicotinamide (HYNIC). 99m Tc-HYNIC-H6F was prepared, and the in vivo characteristics of 99m Tc-HYNIC-H6F were investigated in MDA-MB-453 (HER2-positive) and MDA-MB-231 (HER2-negative) models using small-animal SPECT/CT. Moreover, to investigate the specificity of the H6F peptide toward HER2 and the potential applications in monitoring therapies involving trastuzumab, unlabeled H6F and trastuzumab were used as blocking agents in cell competition studies and SPECT imaging. Results: A standard tricine/trisodium triphenylphosphine-3,39,3$-trisulfonate labeling procedure demonstrated that the radiochemical purity was greater than 95%. 99m Tc-HYNIC-H6F displayed excellent HER2-binding specificity both in vitro and in vivo. SPECT/ CT imaging revealed that the MDA-MB-453 tumors were clearly visualized (percentage injected dose per gram, 3.58 6 0.01 at 30 min after injection), whereas the signals in HER2-negative MDA-MB-231 tumors were much lower (0.73 6 0.22 at 30 min after injection). Tumor uptake of MDA-MB-453 was blocked by the coinjection of excess H6F but not by excess trastuzumab. Conclusion: The 99m Tc-HYNIC-H6F peptide probe specifically accumulates in HER2-positive tumors and is therefore promising for the diagnosis of HER2-positive cancers. Because 99m Tc-HYNIC-H6F and trastuzumab target different regions of the HER2 receptor, this radiotracer also has great potential for monitoring the therapeutic efficacy of trastuzumab by rechecking the expression level of HER2 without blocking effect during therapy. Br east cancer is the most frequent cancer and the second leading cause of cancer death among women worldwide. The great progress in breast cancer screening and early diagnosis in recent decades has significantly increased life expectancy and patient quality of life (1,2). The best-studied tumor-associated antigen in breast cancer is human epidermal growth factor receptor 2 (HER2), which is positive in approximately 20%-30% of all breast cancers (3-5). Moreover, overexpression of HER2 is also characterized as a major negative prognostic factor that is associated with higher mortality in early-stage disease, increased incidence of metastasis, and reduced time to relapse (6-8). Trastuzumab (Herceptin; Genentech), the first approved HER2-targeted humanized monoclonal antibody, is the standard-of-care treatment for patients with HER2-positive breast cancer. In several trials, trastuzumab has proven effective in combination with...

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Structure-based Design of Peptides with High Affinity and Specificity to HER2 Positive Tumors

Cited by 35 publications

References 54 publications

HER2-positive breast cancer targeting and treatment by a peptide-conjugated mini nanodrug

HER2-positive breast cancer targeting and treatment by a peptide-conjugated mini nanodrug

Structure–Activity Relationship of HER2 Receptor Targeting Peptide and Its Derivatives in Targeted Tumor Therapy

SPECT/CT Imaging of the Novel HER2-Targeted Peptide Probe ^99mTc-HYNIC-H6F in Breast Cancer Mouse Models

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Structure-based Design of Peptides with High Affinity and Specificity to HER2 Positive Tumors

Cited by 35 publications

References 54 publications

HER2-positive breast cancer targeting and treatment by a peptide-conjugated mini nanodrug

HER2-positive breast cancer targeting and treatment by a peptide-conjugated mini nanodrug

Structure–Activity Relationship of HER2 Receptor Targeting Peptide and Its Derivatives in Targeted Tumor Therapy

SPECT/CT Imaging of the Novel HER2-Targeted Peptide Probe 99mTc-HYNIC-H6F in Breast Cancer Mouse Models

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SPECT/CT Imaging of the Novel HER2-Targeted Peptide Probe ^99mTc-HYNIC-H6F in Breast Cancer Mouse Models