scholarly journals Paclitaxel-Trastuzumab Mixed Nanovehicle to Target HER2-Overexpressing Tumors

Nanomaterials ◽  
2019 ◽  
Vol 9 (7) ◽  
pp. 948 ◽  
Author(s):  
Celia Nieto ◽  
Ariana Centa ◽  
Jesús A. Rodríguez-Rodríguez ◽  
Atanasio Pandiella ◽  
Eva M. Martín del Valle
Keyword(s):  
Antitumor Activity ◽  
Cancer Cells ◽  
Growth Factor Receptor ◽  
Aqueous Solubility ◽  
Chemotherapeutic Agents ◽  
Her2 Positive ◽  
Targeted Transport ◽  
Epidermal Growth ◽  
Paclitaxel Treatment

Paclitaxel is one of the most widely used chemotherapeutic agents thanks to its effectiveness and broad spectrum of antitumor activity. However, it has a very poor aqueous solubility and a limited specificity. To solve these handicaps, a novel paclitaxel-trastuzumab targeted transport nanosystem has been developed and characterized in this work to specifically treat cancer cells that overexpress the human epidermal growth factor receptor-2 (HER2). Methods: Alginate and piperazine nanoparticles were synthetized and conjugated with paclitaxel:β-cyclodextrins complexes and trastuzumab. Conjugated nanoparticles (300 nm) were characterized and their internalization in HER2-overexpressing tumor cells was analyzed by immunofluorescence. Its specific antitumor activity was studied in vitro using human cell lines with different levels of HER2-expression. Results: In comparison with free paclitaxel:β-cyclodextrins complexes, the developed conjugated nanovehicle presented specificity for the treatment of HER2-overpressing cells, in which it was internalized by endocytosis. Conclusions: It seems that potentially avoiding the conventional adverse effects of paclitaxel treatment could be possible with the use of the proposed mixed nanovehicle, which improves its bioavailability and targets HER2-positive cancer cells.

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, Characterization, and Biological Activity of a Novel Series of Benzo[4,5]imidazo[2,1-b]thiazole Derivatives as Potential Epidermal Growth Factor Receptor Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 682 ◽  
Author(s):  
Xinshan Deng ◽  
Xiaoyu Tan ◽  
Tiantian An ◽  
Qingqing Ma ◽  
Zhe Jin ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cell Lines ◽  
Normal Cell ◽  
Growth Factor Receptor ◽  
Human Cell Line ◽  
Thiazole Derivatives ◽  
Cellular Toxicity ◽  
Epidermal Growth ◽  
Inhibitory Activities

Based on the analysis of epidermal growth factor receptor (EGFR) complexes with gefitinib with molecular docking, the scaffold-hopping strategy, combination of the active substructures, and structural optimization of EGFR inhibitors, a novel series of benzo[4,5]imidazo[2,1-b]thiazole derivatives was designed, synthesized, and evaluated for antitumor activity in human cancer cell lines and cellular toxicity against human normal cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay and EGFR inhibitory activities in vitro. Some target compounds such as 2-(benzo[4,5]imidazo[2,1-b]thiazol-3-yl)-N-(2-hydroxyphenyl)acetamide (D04) and 2-(benzo[4,5]imidazo[2,1-b]thiazol-3-yl)-N-(naphthalen-1-yl)acetamide (D08) have shown significant antitumor activity against the EGFR high-expressed human cell line HeLa. All the target compounds showed hardly any antitumor activity against the EGFR low-expressed human cell line HepG2, and nearly no cellular toxicity against the human normal cell lines HL7702 and human umbilical vein endothelial cell lines (HUVEC). The inhibitory activities against EGFR kinase in vitro of the three target compounds were greatly consistent with the anti-proliferative activities. The preliminary structure–activity relationships of the target compounds were summarized. Conclusively, the novel benzo[4,5]imidazo[2,1-b]thiazole derivatives as novel potential EGFR inhibitors may be used as the potential lead compounds for the development of antitumor agents.

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

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1902 ◽  
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.

scholarly journals Epidermal Growth Factor Receptor: Key to Selective Intracellular Delivery

2020 ◽  
Vol 85 (9) ◽  
pp. 967-993 ◽  
Author(s):  
A. A. Rosenkranz ◽  
T. A. Slastnikova
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cancer Cells ◽  
Targeted Delivery ◽  
Growth Factor Receptor ◽  
Chemotherapeutic Agents ◽  
Egfr Signaling Pathway ◽  
Egfr Activation ◽  
Epidermal Growth

Abstract Epidermal growth factor receptor (EGFR) is an integral surface protein mediating cellular response to a number of growth factors. Its overexpression and increased activation due to mutations is one of the most common traits of many types of cancer. Development and clinical use of the agents, which block EGFR activation, became a prime example of the personalized targeted medicine. However, despite the obvious success in this area, cancer cure remains unattainable in most cases. Because of that, as well as the result of the search for possible ways to overcome the difficulties of treatment, a huge number of new treatment methods relying on the use of EGFR overexpression and its changes to destroy cancer cells. Modern data on the structure, functioning, and intracellular transport of EGFR, its natural ligands, as well as signaling cascades triggered by the EGFR activation, peculiarities of the EGFR expression and activation in oncological disorders, as well as applied therapeutic approaches aimed at blocking EGFR signaling pathway are summarized and analyzed in this review. Approaches to the targeted delivery of various chemotherapeutic agents, radionuclides, immunotoxins, photosensitizers, as well as the prospects for gene therapy aimed at cancer cells with EGFR overexpression are reviewed in detail. It should be noted that increasing attention is being paid nowadays to the development of multifunctional systems, either carrying several different active agents, or possessing several environment-dependent transport functions. Potentials of the systems based on receptor-mediated endocytosis of EGFR and their possible advantages and limitations are discussed.

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

2020 ◽  
Author(s):  
Amal El Amir ◽  
Saniha Ajith ◽  
Nour AlSawaftah ◽  
Waad Abuwatfa ◽  
Debasmita Mukhopadhyay ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Monoclonal Antibody ◽  
Growth Factor Receptor ◽  
Low Frequency ◽  
Chemotherapeutic Agents ◽  
Breast Cancer Cell Lines ◽  
Triggered Release ◽  
Her2 Positive ◽  
Potential Strategy

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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