Ultrasound-triggered Release of Calcein and Doxorubicin from HER2-targeted Liposomes in Breast Cancer Therapy

Abstract The functionalization of liposomes with antibodies is a potential strategy to increase the specificity of liposomes and reduce side-effects of chemotherapeutic agents. The active targeting of Human Epidermal growth factor Receptor 2 (HER2) positive breast cancer cells can be achieved by coating liposomes with an anti-HER2 monoclonal antibody. In this study, we synthesized Calcein and Doxorubicin loaded immunoliposomes functionalized with the monoclonal antibody Trastuzumab. Both liposomes were characterized for size, phospholipid concentration and antibody conjugation. The effect of low-frequency ultrasound (LFUS)-induced drug release was tested using three power densities, 7.46, 9.85 and 17.31 mW/cm2; and the release data were modeled using six different kinetic models. LFUS results established the sonosensitivity of both carrier types, with immunoliposomes being more acoustically sensitive than control liposomes. Results also showed an increase in the release rate as the power density increased from 7.46 to 17.31 mW/cm2. Finally, the in vitro cell experiments showed enhanced uptake and cytotoxicity when breast cancer cell lines, SKBr3 and MDAMB-231, were treated with LFUS-triggered HER-liposomes.

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Ultrasound-triggered herceptin liposomes for breast cancer therapy

Scientific Reports ◽

10.1038/s41598-021-86860-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Amal Elamir ◽

Saniha Ajith ◽

Nour Al Sawaftah ◽

Waad Abuwatfa ◽

Debasmita Mukhopadhyay ◽

...

Keyword(s):

Breast Cancer ◽

Monoclonal Antibody ◽

Growth Factor Receptor ◽

Low Frequency ◽

Chemotherapeutic Agents ◽

Drug Uptake ◽

Phospholipid Content ◽

Her2 Positive ◽

Enhance Efficiency ◽

Potential Strategy

AbstractThe functionalization of liposomes with monoclonal antibodies is a potential strategy to increase the specificity of liposomes and reduce the side-effects associated with chemotherapeutic agents. The active targeting of the Human Epidermal growth factor Receptor 2 (HER2), which is overexpressed in HER2 positive breast cancer cells, can be achieved by coating liposomes with an anti-HER2 monoclonal antibody. In this study, we synthesized calcein and Doxorubicin-loaded immunoliposomes functionalized with the monoclonal antibody Trastuzumab (TRA). Both liposomes were characterized for their size, phospholipid content and antibody conjugation. Exposing the liposomes to low-frequency ultrasound (LFUS) triggered drug release which increased with the increase in power density. Trastuzumab conjugation resulted in enhancing the sensitivity of the liposomes to LFUS. Compared to the control liposomes, TRA-liposomes showed higher cellular toxicity and higher drug uptake by the HER2 + cell line (SKBR3) which was further improved following sonication with LFUS. Combining immunoliposomes with LFUS is a promising technique in the field of targeted drug delivery that can enhance efficiency and reduce the cytotoxicity of antineoplastic drugs.

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Metronomic Chemotherapy for Metastatic Breast Cancer

Oncology Research and Treatment ◽

10.1159/000520236 ◽

2021 ◽

pp. 1-6

Author(s):

Slavomir Krajnak ◽

Marco J. Battista ◽

Annette Hasenburg ◽

Marcus Schmidt

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Growth Factor Receptor ◽

Metastatic Breast ◽

Metronomic Chemotherapy ◽

Best Supportive Care ◽

Chemotherapeutic Agents ◽

Her2 Positive ◽

Continuous Administration ◽

Leading Role

Background: As disease control and quality of life play a leading role in metastatic breast cancer (MBC), metronomic chemotherapy (MCT) is gaining popularity alongside conventional chemotherapy (CCT) and targeted therapies. Summary: MCT, defined as continuous administration of low-dose chemotherapeutic agents, is accepted as a therapy that exerts its effects via immunomodulation, anti-angiogenesis and direct cytotoxic effects. Oral administration of MCT is safe, easy to handle, and allows for flexible drug dosing. Dose accumulations associated with non-tolerable side effects are rare, so the medication can be administered for longer periods of time. Patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic disease resistant to endocrine-based therapy and not requiring rapid tumor response are generally suitable for MCT. However, MCT may also be promising in patients with triple-negative and HER2-positive tumors without aggressive disease who prefer a lower toxicity profile compared to CCT. The most commonly used agents are cyclophosphamide (CTX), methotrexate (MTX), capecitabine (CAPE), and vinorelbine (VRL), whereby a combination of agents is frequently applied. Key Messages: Based on the growing body of evidence, MCT can be considered as a suitable treatment option in selected MBC patients. Nevertheless, there is an urgent need for randomized controlled trials comparing MCT with CCT, but also with best supportive care. Due to the multimodal mechanisms of action, the combination with targeted and immunological therapies may represent a new promising approach for the treatment of MBC.

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Trastuzumab-Modified Gold Nanoparticles Labeled with 211At as a Prospective Tool for Local Treatment of HER2-Positive Breast Cancer

Nanomaterials ◽

10.3390/nano9040632 ◽

2019 ◽

Vol 9 (4) ◽

pp. 632 ◽

Cited By ~ 15

Author(s):

Łucja Dziawer ◽

Agnieszka Majkowska-Pilip ◽

Damian Gaweł ◽

Marlena Godlewska ◽

Marek Pruszyński ◽

...

Keyword(s):

Breast Cancer ◽

Gold Nanoparticles ◽

Local Treatment ◽

Growth Factor Receptor ◽

Dark Field ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Biological Studies ◽

Positive Breast Cancer

Highly localized radiotherapy with radionuclides is a commonly used treatment modality for patients with unresectable solid tumors. Herein, we propose a novel α-nanobrachytherapy approach for selective therapy of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This uses local intratumoral injection of 5-nm-diameter gold nanoparticles (AuNPs) labeled with an α-emitter (211At), modified with polyethylene glycol (PEG) chains and attached to HER2-specific monoclonal antibody (trastuzumab). The size, shape, morphology, and zeta potential of the 5 nm synthesized AuNPs were characterized by TEM (Transmission Electron Microscopy) and DLS (Dynamic Light Scattering) techniques. The gold nanoparticle surface was modified by PEG and subsequently used for antibody immobilization. Utilizing the high affinity of gold for heavy halogens, the bioconjugate was labelled with 211At obtained by α irradiation of the bismuth target. The labeling yield of 211At was greater than 99%. 211At bioconjugates were stable in human serum. Additionally, in vitro biological studies indicated that 211At-AuNP-PEG-trastuzumab exhibited higher affinity and cytotoxicity towards the HER2-overexpressing human ovarian SKOV-3 cell line than unmodified nanoparticles. Confocal and dark field microscopy studies revealed that 211At-AuNP-PEG-trastuzumab was effectively internalized and deposited near the nucleus. These findings show promising potential for the 211At-AuNP-PEG-trastuzumab radiobioconjugate as a perspective therapeutic agent in the treatment of unresectable solid cancers expressing HER2 receptors.

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Trastuzumab-Targeted Biodegradable Nanoparticles for Enhanced Delivery of Dasatinib in HER2+ Metastasic Breast Cancer

Nanomaterials ◽

10.3390/nano9121793 ◽

2019 ◽

Vol 9 (12) ◽

pp. 1793 ◽

Cited By ~ 4

Author(s):

Enrique Niza ◽

María del Mar Noblejas-López ◽

Iván Bravo ◽

Cristina Nieto-Jiménez ◽

José Antonio Castro-Osma ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Therapy ◽

Therapeutic Potential ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Breast Cancer Cell Lines ◽

Her2 Positive ◽

Multikinase Inhibitor ◽

Biodegradable Nanoparticles

Dasatinib (DAS) is a multikinase inhibitor that acts on several signaling kinases. DAS is used as a second-line treatment for chronic accelerated myeloid and Philadelphia chromosome-positive acute lymphoblastic leukemia. The therapeutic potential of DAS in other solid tumours is under evaluation. As for many other compounds, an improvement in their pharmacokinetic and delivery properties would potential augment the efficacy. Antibody-targeted biodegradable nanoparticles can be useful in targeted cancer therapy. DAS has shown activity in human epidermal growth factor receptor 2 (HER2) positive tumors, so conjugation of this compound with the anti-HER2 antibody trastuzumab (TAB) with the use of nanocarriers could improve its efficacy. TAB-targeted DAS-loaded nanoparticles were generated by nanotechnology. The guided nanocarriers enhanced in vitro cytotoxicity of DAS against HER2 human breast cancer cell lines. Cellular mechanistic, release studies and nanoparticles stability were undertaken to provide evidences for positioning DAS-loaded TAB-targeted nanoparticles as a potential strategy for further development in HER2-overexpressing breast cancer therapy.

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A Combination of an Antimitotic and a Bromodomain 4 Inhibitor Synergistically Inhibits the Metastatic MDA-MB-231 Breast Cancer Cell Line

BioMed Research International ◽

10.1155/2019/1850462 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Thandi Mqoco ◽

André Stander ◽

Anna-Mart Engelbrecht ◽

Anna M Joubert

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Line ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Breast Cancer Cells ◽

Chemotherapeutic Agents ◽

Breast Cancer Cell Lines ◽

Mcf 7

Current chemotherapeutic agents have many side effects and are toxic to normal cells, providing impetus to identify agents that can effectively eliminate tumorigenic cells without damaging healthy cells. The aim of this study was to examine whether combining a novel BRD4 inhibitor, ITH-47, with the antimitotic estradiol analogue, ESE-15-ol, would have a synergistic effect on inhibiting the growth of two different breast cancer cell lines in vitro. Our docking and molecular dynamics studies showed that compared to JQ1, ITH-47 showed a similar binding mode with hydrogen bonds forming between the ligand nitrogens of the pyrazole, ASN99, and water of the BRD4 protein. Data from cell growth studies revealed that the GI50 of ITH-47 and ESE-15-ol after 48 hours of exposure was determined to be 15 μM and 70 nM, respectively, in metastatic MDA-MB-231 breast cancer cells. In tumorigenic MCF-7 breast cancer cells, the GI50 of ITH-47 and ESE-15-ol was 75 μM and 60 nM, respectively, after 48 hours of exposure. Furthermore, the combination of 7.5 μM and 14 nM of ITH-47 and ESE-15-ol, respectively, resulted in 50% growth inhibition of MDA-MB-231 cells resulting in a synergistic combination index (CI) of 0.7. Flow cytometry studies revealed that, compared to the control, combination-treated MDA-MB-231 cells had significantly more cells present in the sub-G1 phase and the combination treatment induced apoptosis in the MDA-MB-231 cells. Compared to vehicle-treated cells, the combination-treated cells showed decreased levels of the BRD4, as well as c-Myc protein after 48 hours of exposure. In combination, the selective BRD4 inhibitor, ITH-47, and ESE-15-ol synergistically inhibited the growth of MDA-MB-231 breast cancer cells, but not of the MCF-7 cell line. This study provides evidence that resistance to BRD4 inhibitors may be overcome by combining inhibitors with other compounds, which may have treatment potential for hormone-independent breast cancers.

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Nodular Regenerative Hyperplasia Induced by Trastuzumab Emtansine: Role of Emtansine?

Annals of Hepatology ◽

10.5604/01.3001.0012.2110 ◽

2018 ◽

Vol 17 (5) ◽

pp. 0-10

Author(s):

Marion Lepelley ◽

Marion Allouchery ◽

Jérôme Long ◽

Dorothée Boucherle ◽

Yves Ranchoup ◽

...

Keyword(s):

Breast Cancer ◽

Monoclonal Antibody ◽

Targeted Delivery ◽

Growth Factor Receptor ◽

Cytotoxic Drug ◽

Nodular Regenerative Hyperplasia ◽

Trastuzumab Emtansine ◽

Antibody Drug Conjugate ◽

Her2 Positive ◽

New Formulation

Trastuzumab is a monoclonal antibody targeted against the Human Epidermal Growth Factor Receptor 2 (HER2) overexpressed in some breast cancer. This targeted therapy significantly improves the prognosis of these cancers. Recently an anti-HER2 antibodydrug conjugate was shaped in order to facilitate the targeted delivery of potent cytotoxic drug to cancer cells and to reduce resistance. This formulation, called trastuzumab emtansine (T-DM1), consists of the monoclonal antibody trastuzumab linked to a cytotoxic drug (a derivative of maytansine) via a chemical linker. Little is known about adverse reactions due to this new formulation. Herein we described the case of a woman suffering from a HER2-positive breast cancer, treated with trastuzumab for 30 months followed by T-DM1 monotherapy. After 12 months of T-DM1 treatment, a nodular regenerative hyperplasia confirmed by liver biopsy occurred. T-DM1 was stopped and medical imagery showed a resolution of the nodular regenerative hyperplasia. Unfortunately, hepatic metastasis progressed. Few cases of nodular regenerative hyperplasia induced by T-DM1 have been described so far. Further studies are needed to explore pathogenesis of nodular regenerative hyperplasia with this new antibody-drug conjugate treatment.

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Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2

Pharmaceuticals ◽

10.3390/ph14080791 ◽

2021 ◽

Vol 14 (8) ◽

pp. 791

Author(s):

Irving Balbuena-Rebolledo ◽

Itzia Irene Padilla-Martínez ◽

Martha Cecilia Rosales-Hernández ◽

Martiniano Bello

Keyword(s):

Breast Cancer ◽

Growth Factor Receptor ◽

Md Simulations ◽

New Drugs ◽

Breast Cancer Cell Lines ◽

Vitro Assay ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Potential Inhibitors

Repurposing studies have identified several FDA-approved compounds as potential inhibitors of the intracellular domain of epidermal growth factor receptor 1 (EGFR) and human epidermal receptor 2 (HER2). EGFR and HER2 represent important targets for the design of new drugs against different types of cancer, and recently, differences in affinity depending on active or inactive states of EGFR or HER2 have been identified. In this study, we first identified FDA-approved compounds with similar structures in the DrugBank to lapatinib and gefitinib, two known inhibitors of EGFR and HER2. The selected compounds were submitted to docking and molecular dynamics MD simulations with the molecular mechanics generalized Born surface area approach to discover the conformational and thermodynamic basis for the recognition of these compounds on EGFR and HER2. These theoretical studies showed that compounds reached the ligand-binding site of EGFR and HER2, and some of the repurposed compounds did not interact with residues involved in drug resistance. An in vitro assay performed on two different breast cancer cell lines, MCF-7, and MDA-MB-23, showed growth inhibitory activity for these repurposed compounds on tumorigenic cells at micromolar concentrations. These repurposed compounds open up the possibility of generating new anticancer treatments by targeting HER2 and EGFR.

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ERBB2 mRNA Expression and Response to Ado-Trastuzumab Emtansine (T-DM1) in HER2-Positive Breast Cancer

Cancers ◽

10.3390/cancers12071902 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1902 ◽

Cited By ~ 1

Author(s):

Gaia Griguolo ◽

Fara Brasó-Maristany ◽

Blanca González-Farré ◽

Tomás Pascual ◽

Núria Chic ◽

...

Keyword(s):

Breast Cancer ◽

Growth Factor Receptor ◽

Trastuzumab Emtansine ◽

Her2 Positive ◽

Erbb2 Expression ◽

Erbb2 Mrna ◽

Cancer Types ◽

Epidermal Growth ◽

Tcga Dataset

Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy; however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene (ERBB2) mRNA. We analyzed ERBB2 expression using a clinically applicable assay in formalin-fixed paraffin-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of ERBB2 levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally, ERBB2 expression was explored in 392 BCs from an in-house dataset, 368 primary BCs from The Cancer Genome Atlas (TCGA) dataset and 10,071 tumors representing 33 cancer types from the PanCancer TCGA dataset. High ERBB2 mRNA was found associated with better response and progression-free survival in the metastatic setting and higher rates of pathological complete response in the neoadjuvant setting. ERBB2 expression also correlated with in vitro response to T-DM1. Finally, our assay identified 0.20–8.41% of tumors across 15 cancer types as ERBB2-high, including gastric and esophagus adenocarcinomas, urothelial carcinoma, cervical squamous carcinoma and pancreatic cancer. In particular, we identified high ERBB2 mRNA in a patient with HER2+ advanced gastric cancer who achieved a long-lasting partial response to T-DM1. Our study demonstrates that the heterogeneity in response to T-DM1 is partly explained by ERBB2 levels and provides a clinically applicable assay to be tested in future clinical trials of breast cancer and other cancer types.

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Trastuzumab-Coated Nanoparticles Loaded With Docetaxel for Breast Cancer Therapy

Dose-Response ◽

10.1177/1559325819872583 ◽

2019 ◽

Vol 17 (3) ◽

pp. 155932581987258 ◽

Cited By ~ 7

Author(s):

Xueyan Zhang ◽

Jiaxin Liu ◽

Xiangyu Li ◽

Fang Li ◽

Robert J. Lee ◽

...

Keyword(s):

Breast Cancer ◽

Growth Factor Receptor ◽

Tween 80 ◽

Hybrid Nanoparticles ◽

Hydrophobic Core ◽

Mcf7 Cells ◽

Her2 Positive ◽

Coated Nanoparticles ◽

Polymer Hybrid

Docetaxel (DTX) is commonly used for breast cancer treatment. Tween 80 used for DTX dissolution in its clinical formulation causes severe hypersensitivity and other adverse reactions. In this study, trastuzumab (Tmab)-coated lipid-polymer hybrid nanoparticles (PLNs) were prepared, composed of poly (d, l-lactide- co-glycolide), PLGA; polyethylenimine (PEI); and lipids. The PLGA/PEI/lipid formed a hydrophobic core, while Tmab was electrostatically adsorbed on the surface of the PLNs as a ligand that targets human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells. The resulting PLNs, electrostatically adsorbed Tmab-bearing PLGA/PEI/lipid nanoparticles (eTmab-PPLNs), had a mean particle size of 217.4 ± 13.36 nm, a ζ potential of 0.056 ± 0.315 mV, and good stability. In vitro, the eTmab-PPLNs showed increased cytotoxicity in HER2-postive BT474 cells but not in HER2-negative MCF7 cells. Studies of the ability of eTmab-PPLNs to target HER2 were performed. The uptake of eTmab-PPLNs was shown to be dependent on HER2 expression level. Therefore, eTmab-PPLNs provide a promising therapeutic for the treatment of breast cancer.

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