scholarly journals Humanized Bispecific Antibody (mPEG×HER2) Rapidly Confers PEGylated nanoaparticles Tumor Specificity for Multimodality Imaging in Breast Cancer

2020 ◽  
Author(s):  
Yi-An Cheng ◽  
Tung-Ho Wu ◽  
Yun-Ming Wang ◽  
Tian-Lu Cheng ◽  
I-Ju Chen ◽  
...  
Keyword(s):  
Bispecific Antibody ◽  
Multimodality Imaging ◽  
Growth Factor Receptor ◽  
Her2 Positive ◽  
Specific Targeting ◽  
Enhanced Sensitivity ◽  
Specificity And Sensitivity ◽  
Methoxypolyethylene Glycol ◽  
One Step

Abstract Background: Developing a universal strategy to improve the specificity and sensitivity of PEGylated nanoaparticles (PEG-NPs) for assisting in the diagnosis of tumors is important in multimodality imaging. Here, we developed the anti-methoxypolyethylene glycol (mPEG) bispecific antibody (BsAb; mPEG×HER2), which has dual specificity for mPEG and human epidermal growth factor receptor 2 (HER2), with a diverse array of PEG-NPs to confer nanoparticles with HER2 specificity and stronger intensity. Result: We used a one-step formulation to rapidly modify the nanoprobes with mPEG×HER2 and optimized the modified ratio of BsAbs on several PEG-NPs (Lipo-DiR, SPIO, Qdot and AuNP). The αHER2/PEG-NPs could specifically target MCF7/HER2 cells (HER2+) but not MCF7/neo1 cells (HER2-). The αHER2/Lipo-DiR and αHER2/SPIO could enhance the sensitivity of untargeted PEG-NPs on MCF7/HER2 (HER2+). In in vivo imaging, αHER2/Lipo-DiR and αHER2/SPIO increased the specific targeting and enhanced mPEG-nanoprobe accumulation 161% and 187%, respectively, in HER2-overexpressing tumors. Conclusion: mPEG×HER2, therefore, provided a simple one-step formulation to confer HER2-specific targeting and enhanced sensitivity and contrast intensity on HER2 positive tumors for multimodality imaging.

scholarly journals Imaging-Guided Therapy Simultaneously Targeting HER2 and EpCAM with Trastuzumab and EpCAM-Directed Toxin Provides Additive Effect in Ovarian Cancer Model

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3939
Author(s):  
Tianqi Xu ◽  
Anzhelika Vorobyeva ◽  
Alexey Schulga ◽  
Elena Konovalova ◽  
Olga Vorontsova ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Growth Factor Receptor ◽  
Repeated Administration ◽  
Ovarian Cancer Cells ◽  
Her2 Positive ◽  
Efficient Treatment ◽  
Pseudomonas Exotoxin A ◽  
Epidermal Growth

Efficient treatment of disseminated ovarian cancer (OC) is challenging due to its heterogeneity and chemoresistance. Overexpression of human epidermal growth factor receptor 2 (HER2) and epithelial cell adhesion molecule (EpCAM) in approx. 30% and 70% of ovarian cancers, respectively, allows for co-targeted treatment. The clinical efficacy of the monoclonal antibody trastuzumab in patients with HER2-positive breast, gastric and gastroesophageal cancers makes it readily available as the HER2-targeting component. As the EpCAM-targeting component, we investigated the designed ankyrin repeat protein (DARPin) Ec1 fused to a truncated variant of Pseudomonas exotoxin A with reduced immunogenicity and low general toxicity (LoPE). Ec1-LoPE was radiolabeled, evaluated in ovarian cancer cells in vitro and its biodistribution and tumor-targeting properties were studied in vivo. The therapeutic efficacy of Ec1-LoPE alone and in combination with trastuzumab was studied in mice bearing EpCAM- and HER2-expressing SKOV3 xenografts. SPECT/CT imaging enabled visualization of EpCAM and HER2 expression in the tumors. Co-treatment using Ec1-LoPE and trastuzumab was more effective at reducing tumor growth and prolonged the median survival of mice compared with mice in the control and monotherapy groups. Repeated administration of Ec1-LoPE was well tolerated without signs of hepatic or kidney toxicity. Co-treatment with trastuzumab and Ec1-LoPE might be a potential therapeutic strategy for HER2- and EpCAM-positive OC.

scholarly journals Synthesis of site-specific antibody-drug conjugates by ADP-ribosyl cyclases

2020 ◽  
Vol 6 (23) ◽  
pp. eaba6752 ◽  
Author(s):  
Zhefu Dai ◽  
Xiao-Nan Zhang ◽  
Fariborz Nasertorabi ◽  
Qinqin Cheng ◽  
Jiawei Li ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Reaction Times ◽  
Single Step ◽  
Her2 Positive ◽  
Site Specific ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Most of the current antibody-drug conjugates (ADCs) in clinic are heterogeneous mixtures. To produce homogeneous ADCs, established procedures often require multiple steps or long reaction times. The introduced mutations or foreign sequences may cause high immunogenicity. Here, we explore a new concept of transforming CD38 enzymatic activity into a facile approach for generating site-specific ADCs. This was achieved through coupling bifunctional antibody-CD38 fusion proteins with designer dinucleotide-based covalent inhibitors with stably attached payloads. The resulting adenosine diphosphate–ribosyl cyclase–enabled ADC (ARC-ADC) with a drug-to-antibody ratio of 2 could be rapidly generated through single-step conjugation. The generated ARC-ADC targeting human epidermal growth factor receptor 2 (HER2) displays excellent stability and potency against HER2-positive breast cancer both in vitro and in vivo. This proof-of-concept study demonstrates a new strategy for production of site-specific ADCs. It may provide a general approach for the development of a novel class of ADCs with potentially enhanced properties.

Dimeric Her2-Specific Affibody Mediated Cisplatin-Loaded Nanoparticles for Tumor Enhanced Chemo-Radiotherapy

2021 ◽  
Author(s):  
Haijun Wang ◽  
Dianlong Jia ◽  
Dandan Yuan ◽  
Xiaolei Yin ◽  
Fengjiao Yuan ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Tumor Cells ◽  
Combined Therapy ◽  
Expression System ◽  
Growth Factor Receptor ◽  
High Energy ◽  
Tumor Growth Inhibition ◽  
Ros Generation ◽  
Her2 Positive

Abstract Background: Solid tumor hypoxic conditions fails to facilitate reactive oxygen species (ROS) generation and formation of DNA double-strand breaks (DSBs) induced by ionizing radiation, ultimately lead to a crucial role in radiotherapy resistance. Recently, there have been significant technical advances in nanomedicine aid to relieve hypoxia by in situ production of O2, serving as “radiosensitizer” to induce tumor cells more sensitive to ionizing radiation. However, the off-target damage of surrounding healthy tissues caused by such high-energy radiation is often unavoidable and the tumor cells at some distance from the focal spot of ionizing radiation may avoid damage. Therefore, there is an urgent need to exploit an intelligently targeted nanoplatform to integrate both precisely enhance RT-induced DNA damage and combined therapy.Results: Herein, we developed human epidermal growth factor receptor 2 (Her2)-specific dimeric affibody (ZHer2) mediated cisplatin-loaded mesoporous polydopamine/MnO2/polydopamine nanoparticles (Pt@mPDA/MnO2/PDA-ZHer2 NPs) for MRI and enhanced chemo-radiotherapy of Her2-positive ovarian tumor. These NPs are biodegradable under simulated tumor microenvironment, resulting in cisplatin accelerated release, as well as production of O2. ZHer2 produced by the E. coli expression system endowed NPs with Her2-dependent binding ability in the Her2-positive SKOV-3 cells. In vivo MRI studies revealed an obvious T1 contrast enhancement at the tumor site. Moreover, these NPs achieved efficient tumor homing and penetration, attributing to the efficient internalization and penetrability of ZHer2. Under X-Ray irradiation, these NPs exhibited the highest tumor growth inhibition effect. Immunofluorescence assay showed these NPs significantly reduced the expression of HIF-1α and improved ROS level, resulting in radiosensitization. Conclusions: The nanocarriers constructed in this study integrated Her2 targeting, diagnosis, RT sensitization, thus providing a new idea for clinical translation in tumor theranostics.

scholarly journals Strengthening Gastric Cancer Therapy by Trastuzumab-Conjugated Nanoparticles with Simultaneous Encapsulation of Anti-MiR-21 and 5-Fluorouridine

2017 ◽  
Vol 44 (6) ◽  
pp. 2158-2173 ◽  
Author(s):  
Nan Hu ◽  
Jun Feng  Yin ◽  
Ze Ji ◽  
Yidong Hong ◽  
Puyuan Wu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cellular Uptake ◽  
Photoelectron Spectroscopy ◽  
Growth Factor Receptor ◽  
Double Emulsion ◽  
Her2 Receptor ◽  
Her2 Positive ◽  
Antitumor Effects

Background/Aims: MicroRNA-21 is an oncogenic miR (oncomiR) frequently elevated in gastric cancer (GC). Overexpression of miR-21 decreases the sensitivity of GC cells to 5-fluorouridine (5-Fu) and trastuzumab, a humanized monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2). Receptor-mediated endocytosis plays a crucial role in the delivery of biotherapeutics including anti-miRNA oligonucleotides (AMOs). This study is a continuation of earlier findings involving poly(ε-caprolactone) (PCL)-poly (ethylene glycol) (PEG) nanoparticles (PEG-PCL NPs), which were coated with trastuzumab to target GC with HER2 receptor over-expression using anti-miRNA-21 (AMO-21) and 5-Fu. Methods: HER-PEG-PCL NPs were prepared by one-step carbodiimide coupling using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAc) and Sulfo-NHS in aqueous phase. Covalent coupling of amino groups at the surface of PEG-PCL with the carboxyl groups of trastuzumab was analyzed by X-ray photoelectron spectroscopy (XPS). AMO-21/5-Fu NPs were formulated by a double-emulsion solvent evaporation technique. The cell line specificity, cellular uptake and AMO-21 delivery were investigated through the rhodamine-B-labeled 6-carboxyfluorescein (FAM)-AMO-21-PEG-PCL NPs coated with or without the antibody in both Her2-positive (NUGC4) and negative GC cells (SGC7901) visualized by fluorescence microscopy. The cytotoxicity of the HER-PEG-PCL NPs encapsulating AMO-21 was evaluated by MTT and apoptosis. Real-time reverse-transcription polymerase chain reaction (RT-PCR) was used to examine miR-21 and phosphatase and tensin homolog (PTEN) and Sprouty2 expression in GC cell lines. The antitumor effects of AMO-21/5-Fu NPs were compared with other groups in xenograft gastric cancer mice. Results: The antibody conjugates significantly enhanced the cellular uptake of NPs. The AMO-21/5-Fu NPs effectively suppressed the target miRNA expression in GC cells, which further up-regulated PTEN and Sprouty2. As a result, the sensitivity of HER2-expressing gastric cancer to trastuzumab and 5-Fu were enhanced both in vitro and in vivo. The approach enhanced the targeting by trastuzumab as well as antibody-dependent cellular cytotoxicity (ADCC) of immune effector cells Conclusions: Taken together, the results provide insight into the biological and clinical potential of targeted AMO-21 and 5-Fu co-delivery using modified trastuzumab for GC treatment.

scholarly journals Observations on the Effects of Residualization and Dehalogenation on the Utility of N-Succinimidyl Ester Acylation Agents for Radioiodination of the Internalizing Antibody Trastuzumab

Molecules ◽  
2019 ◽  
Vol 24 (21) ◽  
pp. 3907 ◽  
Author(s):  
Satish K. Chitneni ◽  
Eftychia Koumarianou ◽  
Ganesan Vaidyanathan ◽  
Michael R. Zalutsky
Keyword(s):  
Growth Factor Receptor ◽  
Carcinoma Cells ◽  
Breast Cancers ◽  
Human Breast ◽  
Her2 Positive ◽  
Two Factors ◽  
Epidermal Growth ◽  
Prolonged Retention ◽  
Human Breast Carcinoma Cells

Trastuzumab is an antibody used for the treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancers. Since trastuzumab is an internalizing antibody, two factors could play an important role in achieving high uptake and prolonged retention of radioactivity in HER2-positive tumors after radioiodination—residualizing capacity after receptor-mediated internalization and susceptibility to dehalogenation. To evaluate the contribution of these two factors, trastuzumab was radiolabeled using the residualizing reagent N-succinimidyl 4-guanidinomethyl-3-[*I]iodobenzoate ([*I]SGMIB) and the nonresidualizing reagent N-succinimidyl-3-[*I]iodobenzoate ([*I]SIB), both of which are highly dehalogenation-resistant. Paired-label uptake and intracellular retention of [125I]SGMIB-trastuzumab and [131I]SIB-trastuzumab was compared on HER2-expressing BT474 human breast carcinoma cells. Tumor uptake and normal tissue distribution characteristics for the two labeled conjugates were assessed in mice bearing BT474M1 xenografts. The internalization and intracellular retention of initially-bound radioactivity in BT474 cells was similar for the two labeled conjugates up to 4 h, but were significantly higher for [125I]SGMIB-trastuzumab at 6 and 24 h. Similarly, [*I]SGMIB labeling resulted in significantly higher uptake and retention of radioactivity in BT474M1 xenografts at all studied time points. Moreover, tumor-to-tissue ratios for [125I]SGMIB-trastuzumab were consistently higher than those for [131I]SIB-trastuzumab starting at 12 h postinjection. Thus, optimal targeting of HER2-positive breast cancers with a radioiodinated trastuzumab conjugate requires an acylation agent that imparts residualizing capacity in addition to high stability towards dehalogenation in vivo.

scholarly journals Dimeric Her2-specific affibody mediated cisplatin-loaded nanoparticles for tumor enhanced chemo-radiotherapy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Haijun Wang ◽  
Dianlong Jia ◽  
Dandan Yuan ◽  
Xiaolei Yin ◽  
Fengjiao Yuan ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Tumor Cells ◽  
Focal Point ◽  
Combined Therapy ◽  
Expression System ◽  
Growth Factor Receptor ◽  
High Energy ◽  
Immunofluorescence Assay ◽  
Her2 Positive

Abstract Background Solid tumor hypoxic conditions prevent the generation of reactive oxygen species (ROS) and the formation of DNA double-strand breaks (DSBs) induced by ionizing radiation, which ultimately contributes to radiotherapy (RT) resistance. Recently, there have been significant technical advances in nanomedicine to reduce hypoxia by facilitating in situ O2 production, which in turn serves as a “radiosensitizer” to increase the sensitivity of tumor cells to ionizing radiation. However, off-target damage to the tumor-surrounding healthy tissue by high-energy radiation is often unavoidable, and tumor cells that are further away from the focal point of ionizing radiation may avoid damage. Therefore, there is an urgent need to develop an intelligent targeted nanoplatform to enable precise enhanced RT-induced DNA damage and combined therapy. Results Human epidermal growth factor receptor 2 (Her2)-specific dimeric affibody (ZHer2) mediated cisplatin-loaded mesoporous polydopamine/MnO2/polydopamine nanoparticles (Pt@mPDA/MnO2/PDA-ZHer2 NPs) for MRI and enhanced chemo-radiotherapy of Her2-positive ovarian tumors is reported. These NPs are biodegradable under a simulated tumor microenvironment, resulting in accelerated cisplatin release, as well as localized production of O2. ZHer2, produced using the E. coli expression system, endowed NPs with Her2-dependent binding ability in Her2-positive SKOV-3 cells. An in vivo MRI revealed obvious T1 contrast enhancement at the tumor site. Moreover, these NPs achieved efficient tumor homing and penetration via the efficient internalization and penetrability of ZHer2. These NPs exhibited excellent inhibition of tumor growth with X-ray irradiation. An immunofluorescence assay showed that these NPs significantly reduced the expression of HIF-1α and improved ROS levels, resulting in radiosensitization. Conclusions The nanocarriers described in the present study integrated Her2 targeting, diagnosis and RT sensitization into a single platform, thus providing a novel approach for translational tumor theranostics. Graphic abstract

scholarly journals Circulating and Intracellular miRNAs as Prognostic and Predictive Factors in HER2-Positive Early Breast Cancer Treated with Neoadjuvant Chemotherapy: A Review of the Literature

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4894
Author(s):  
Chrystel Isca ◽  
Federico Piacentini ◽  
Ilenia Mastrolia ◽  
Valentina Masciale ◽  
Federica Caggia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor Receptor ◽  
Treatment Resistance ◽  
Her2 Positive ◽  
Diagnostic Biomarkers ◽  
Small Noncoding Rnas ◽  
Epidermal Growth ◽  
Predictive And Prognostic Value ◽  
Prognostic And Predictive Factors

MicroRNAs (miRNA) are small noncoding RNAs that can act as both oncogene and tumor suppressors. Deregulated miRNA expression has been detected in human cancers, including breast cancer (BC). Considering their important roles in tumorigenesis, miRNAs have been investigated as potential prognostic and diagnostic biomarkers. Neoadjuvant setting is an optimal model to investigate in vivo the mechanism of treatment resistance. In the management of human epidermal growth factor receptor-2 (HER2)-positive early BC, the anti-HER2-targeted therapies have drastically changed the survival outcomes. Despite this, growing drug resistance due to the pressure of therapy is relatively frequent. In the present review, we focused on the main miRNAs involved in HER2-positive BC tumorigenesis and discussed the recent evidence on their predictive and prognostic value.

scholarly journals Structural and Electrophysiological Changes in a Model of Cardiotoxicity Induced by Anthracycline Combined With Trastuzumab

2021 ◽  
Vol 12 ◽  
Author(s):  
Claudia Altomare ◽  
Alessandra Maria Lodrini ◽  
Giuseppina Milano ◽  
Vanessa Biemmi ◽  
Edoardo Lazzarini ◽  
...  
Keyword(s):  
Combined Therapy ◽  
Combined Treatment ◽  
Growth Factor Receptor ◽  
Left Ventricular ◽  
Her2 Positive ◽  
Adult Rats ◽  
Adaptive Changes ◽  
Two Agents ◽  
Intracellular Ca

BackgroundCombined treatment with anthracyclines (e.g., doxorubicin; Dox) and trastuzumab (Trz), a humanized anti-human epidermal growth factor receptor 2 (HER2; ErbB2) antibody, in patients with HER2-positive cancer is limited by cardiotoxicity, as manifested by contractile dysfunction and arrhythmia. The respective roles of the two agents in the cardiotoxicity of the combined therapy are incompletely understood.ObjectiveTo assess cardiac performance, T-tubule organization, electrophysiological changes and intracellular Ca2+ handling in cardiac myocytes (CMs) using an in vivo rat model of Dox/Trz-related cardiotoxicity.Methods and ResultsAdult rats received 6 doses of either Dox or Trz, or the two agents sequentially. Dox-mediated left ventricular (LV) dysfunction was aggravated by Trz administration. Dox treatment, but not Trz, induced T-tubule disarray. Moreover, Dox, but not Trz monotherapy, induced prolonged action potential duration (APD), increased incidence of delayed afterdepolarizations (DADs) and beat-to-beat variability of repolarization (BVR), and slower Ca2+ transient decay. Although APD, DADs, BVR and Ca2+ transient decay recovered over time after the cessation of Dox treatment, subsequent Trz administration exacerbated these abnormalities. Trz, but not Dox, reduced Ca2+ transient amplitude and SR Ca2+ content, although only Dox treatment was associated with SERCA downregulation. Finally, Dox treatment increased Ca2+ spark frequency, resting Ca2+ waves, sarcoplasmic reticulum (SR) Ca2+ leak, and long-lasting Ca2+ release events (so-called Ca2+ “embers”), partially reproduced by Trz treatment.ConclusionThese results suggest that in vivo Dox but not Trz administration causes T-tubule disarray and pronounced changes in electrical activity of CMs. While adaptive changes may account for normal AP shape and reduced DADs late after Dox administration, subsequent Trz administration interferes with such adaptive changes. Intracellular Ca2+ handling was differently affected by Dox and Trz treatment, leading to SR instability in both cases. These findings illustrate the specific roles of Dox and Trz, and their interactions in cardiotoxicity and arrhythmogenicity.

scholarly journals Drug Conjugates Based on a Monovalent Affibody Targeting Vector Can Efficiently Eradicate HER2 Positive Human Tumors in an Experimental Mouse Model

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 85
Author(s):  
Tianqi Xu ◽  
Haozhong Ding ◽  
Anzhelika Vorobyeva ◽  
Maryam Oroujeni ◽  
Anna Orlova ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Experimental Therapy ◽  
Complete Regression ◽  
Her2 Positive ◽  
Drug Conjugate ◽  
Drug Conjugates ◽  
Ic50 Values ◽  
Targeting Vector

The human epidermal growth factor receptor 2 (HER2) is frequently overexpressed in a variety of cancers and therapies targeting HER2 are routinely used in the clinic. Recently, small engineered scaffold proteins, such as affibody molecules, have shown promise as carriers of cytotoxic drugs, and these drug conjugates may become complements or alternatives to the current HER2-targeting therapies. Here, we investigated if a monovalent HER2-binding affibody molecule, ZHER2:2891, fused with a plasma half-life extending albumin binding domain (ABD), may be used as carrier of the cytotoxic maytansine derivate mcDM1. We found that the resulting drug conjugate, ZHER2:2891-ABD-E3-mcDM1, had strong affinity for its cognate molecular targets: HER2 and serum albumin. ZHER2:2891-ABD-E3-mcDM1 displayed potent cytotoxic activity towards cells with high HER2 expression, with IC50 values ranging from 0.6 to 33 nM. In vivo, an unspecific increase in uptake in the liver, imparted by the hydrophobic mcDM1, was counteracted by incorporation of hydrophilic and negatively charged glutamate residues near the site of mcDM1 conjugation. A dose-escalation experiment showed that increasing doses up to 15.1 mg/kg gave a proportional increase in uptake in xenografted HER2-overexpressing SKOV3 tumors, after which the tumors became saturated. Experimental therapy with four once-weekly injection of 10.3 or 15.1 mg/kg led to efficient regression of tumors in all animals and complete regression in some. Weight loss was detected for some animals in the group receiving the highest dose, suggesting that it was close to the maximum tolerated dose. In conclusion, the monovalent HER2-targeting affibody drug conjugate presented herein have potent anti-tumor activity in vivo.

scholarly journals Self-Assembled Nanomicelles of Affibody-Drug Conjugate with Excellent Therapeutic Property to Cure Ovary and Breast Cancers

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xuelin Xia ◽  
Xiaoyuan Yang ◽  
Wei Huang ◽  
Xiaoxia Xia ◽  
Deyue Yan
Keyword(s):  
Cancer Therapy ◽  
Self Assembly ◽  
Targeted Delivery ◽  
Growth Factor Receptor ◽  
Circulation Time ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Drug Conjugate ◽  
Self Assembled

AbstractAffibody molecules are small non-immunoglobulin affinity proteins, which can precisely target to some cancer cells with specific overexpressed molecular signatures. However, the relatively short in vivo half-life of them seriously limited their application in drug targeted delivery for cancer therapy. Here an amphiphilic affibody-drug conjugate is self-assembled into nanomicelles to prolong circulation time for targeted cancer therapy. As an example of the concept, the nanoagent was prepared through molecular self-assembly of the amphiphilic conjugate of ZHER2:342-Cys with auristatin E derivate, where the affibody used is capable of binding to the human epidermal growth factor receptor 2 (HER2). Such a nanodrug not only increased the blood circulation time, but also enhanced the tumor targeting capacity (abundant affibody arms on the nanoagent surface) and the drug accumulation in tumor. As a result, this affibody-based nanoagent showed excellent antitumor activity in vivo to HER2-positive ovary and breast tumor models, which nearly eradicated both small solid tumors (about 100 mm3) and large established tumors (exceed 500  mm3). The relative tumor proliferation inhibition ratio reaches 99.8% for both models.

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