HER2 Targeting Peptides Screening and Applications in Tumor Imaging and Drug Delivery

Geng, Li; Wang, Zihua; Jia, Xiangqian; Han, Qiuju; Xiang, Zhichu; Li, Dan; Yang, Xiaoliang; Zhang, Di; Bu, Xiangli; Wang, Weizhi; Hu, Zhiyuan; Fang, Qiaojun

doi:10.7150/thno.14302

Cited by 48 publications

(32 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…The other chosen peptide (GYYNPN), derived from the MD simulation and refined by creating an OBOC library [22], was also measured alone or in combination with the first sequence. Here, in order to prevent succinimide formation, we replaced the last amino acid of the sequence with threonine, which, in this position, was the second most frequent amino acid after asparagineamong the 72 verified positive sequences [22]. The corresponding sequences and codes can be seen in Table 1.…”

Section: Peptide Synthesismentioning

confidence: 99%

“…After screening and sequencing, peptide affinity and specificity were analyzed. This resulted in the obtainment of 72 highly similar 17-mer peptides with a high binding affinity to the HER2 receptor [22]. The central part of these peptides was rather conservative, while the terminals showed a bit more variability.…”

Section: Introductionmentioning

confidence: 99%

“…The central part of these peptides was rather conservative, while the terminals showed a bit more variability. Among them, CDTFPYLGWWNPNEYRY and CKTIYYLGYYNPNEYRY showed the highest affinity to HER2 [22]. As the N-terminal part of the peptides (especially the latter one) showed similarities with the KCCYSL peptide, so we decided to synthesize combined peptides where the modified KCCYSL sequence precedes GYYNPN.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2020

View full text Add to dashboard Cite

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. ...

show abstract

“…Peptide conjugation is one adopted approach that takes advantage of the multitude of peptides' biological roles, providing highly specific ligands that target particular cell receptors and sequences that can improve cellular uptake and avoid drug resistance mechanisms5-8. Furthermore, the conjugation of peptides that can lead to potential supramolecular assembly behavior has become a notable extension of this over the last decade9-17.…”

Section: Introductionmentioning

confidence: 99%

Drug-Bearing Supramolecular Filament Hydrogels as Anti-Inflammatory Agents

et al. 2017

View full text Add to dashboard Cite

We report here on the covalent conversion of the anti-inflammatory agent ketoprofen into self-assembling prodrugs that enable the effective purification of ketoprofen enantiomers, the improved selectivity and potency of ketoprofen, as well as the formation of one-component drug-bearing supramolecular hydrogels. We found that the ketoprofen hydrogelator could exhibit much-enhanced selectivity for cyclooxygenase 2 (COX-2) over COX-1, reduce the concentration of inflammatory cytokines (IL-1 and TNFα), and induce apoptosis in fibroblast-like synoviocytes while maintaining biocompatibility with healthy chondrocytes. In addition, these anti-inflammatory agent-containing hydrogels demonstrated the ability to retain the therapeutic within a joint cavity after intra-articular injection, exhibiting a slow, steady release into the plasma. We believe that upon further optimization these drug-based injectable supramolecular hydrogels could provide the basis for a local treatment strategy for rheumatoid arthritis and similar conditions.

show abstract

HER2 Targeting Peptides Screening and Applications in Tumor Imaging and Drug Delivery

Cited by 48 publications

References 39 publications

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

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

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

Drug-Bearing Supramolecular Filament Hydrogels as Anti-Inflammatory Agents

Contact Info

Product

Resources

About

HER2 Targeting Peptides Screening and Applications in Tumor Imaging and Drug Delivery

Cited by 48 publications

References 39 publications

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

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

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

Drug-Bearing Supramolecular Filament Hydrogels as Anti-Inflammatory Agents

Contact Info

Product

Resources

About

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

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