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Nanoparticulate Systems for Lung Cancer Targeted Therapy
Published in Devarajan Thangadurai, Saher Islam, Jeyabalan Sangeetha, Natália Cruz-Martins, Biogenic Nanomaterials, 2023
Ana Cláudia Pimenta, Luísa Nascimento, Natália Cruz-Martins
Antibodies and antibody fragments are attractive ligands for active targeted delivery. They exhibit both high binding affinity and high specificity for cell receptors. The use of antibody as a targeting ligand is expensive, its production is time-consuming, storage and stability are of concern, and there are issues in terms of immunogenicity. Cetuximab is an IgG monoclonal antibody that binds to EGFR overexpressed in cancer cells, previously applied to treat advanced NSCLC. About 40% to 80% of NSCLCs show a high EGFR expression, which makes this molecule an interesting target. Conjugates of Cetuximab to paclitaxel, gemcitabine or docetaxel loaded NPs are being tested, showing encouraging in vivo results with mice models. Conjugates of cetuximab and liposomes have been tried to deliver siRNA. In general, it has been achieved an improved drug uptake by cancer cells, along with lower toxicity. Matuzumab, another EGFR antibody, is conjugated to magnetic NPs to achieve higher tumor cell capture efficiency. A few studies have shown better outcomes in mice, mainly with smaller tumor mass.
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Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Eun-Kyung Lim, Taekhoon Kim, Soonmyung Paik, Seungjoo Haam, Yong-Min Huh, Kwangyeol Lee
Tyrosine kinases that are responsible for activation of signal transduction cascades can be inhibited by tyrosine kinase inhibitors. These are used as anticancer drugs by competing with ATP [211]. About 15%–20% of patients with early-stage breast cancer have tumors that overexpress or amplify HER2 genes, which is associated with increased proliferation of cancer cells and poor prognosis [390–394]. When HER2 binds to the ligands (preferably forming dimers), the HER2 pathway can initiate the mitogen-activated protein kinase pathway as well as the PI3K/Akt pathway, which in turn activates the nuclear factor kappa B pathway. When growth factors bind to their receptors on the cell surface, the receptors give a signal causing cell division. However, if growth factor receptor inhibitors bind to their receptors, the receptors no longer cause uncontrolled cell proliferation. Trastuzumab (Herceptin) is a HER2-specific mAb and the only approved HER2-targeted drug. Cells targeted with trastuzumab experience cell cycle arrest in the G phase; thus, cell proliferation is reduced by downregulation of HER2/neu [383, 384]. When cancer develops it requires generation of neovasculature for nutrient and oxygen supply. Trastuzumab suppresses angiogenesis, formation of new blood vessels, by both induction of antiangiogenic factors and repression of proangiogenic factors. Cetuximab (Erbitux), an EGFR inhibitor, binds to EGFR and inhibits uncontrolled growth of cancers with EGFR mutations [215, 216, 395–400].
Emerging Trends in Nanotechnology for Diagnosis and Therapy of Lung Cancer
Published in Alok Dhawan, Sanjay Singh, Ashutosh Kumar, Rishi Shanker, Nanobiotechnology, 2018
Nanda Rohra, Manish Gore, Sathish Dyawanapelly, Mahesh Tambe, Ankit Gautam, Meghna Suvarna, Ratnesh Jain, Prajakta Dandekar
Naked mAbs work individually and are the most common type of mAb used in cancer treatment. These bind to cancer-specific antigens and work either by acting as a marker for the body's immune system to destroy them or by blocking antigens on cancer cells (or other nearby cells) that help cancer cells grow or spread (American Chemical Society 2016a). Cetuximab (Erbitux) is an example of a naked mAb that targets the epidermal growth factor receptor (EGFR) and is being tested in a phase II trial for patients with stage IIIB non-small cell lung cancer (American Chemical Society 2016c). Cetuximab in combination with carboplatin and gemcitabine resulted in a higher response rate (RR) of 27.7% and longer progression-free survival (PFS) of 5.09 months as opposed to the RR (18.2%) and PFS (4.21 months) observed with chemotherapy alone in a phase II trial conducted on patients with advanced NSCLC (Sgambato et al. 2014).
Cetuximab-conjugated perfluorohexane/gold nanoparticles for low intensity focused ultrasound diagnosis ablation of thyroid cancer treatment
Published in Science and Technology of Advanced Materials, 2020
Yue Ma, Xiaoshan Peng, Lingling Wang, Haixia Li, Wen Cheng, Xiulan Zheng, Ying Liu
Several reports have shown that overexpression of the epidermal growth factor receptor (EGFR) is strongly associated with tumour progression, migration, and invasion. EGFR is common in ATC patients [18] and antibodies or small molecules based on EGFR immunotherapy can significantly increase the therapeutic effect against this cancer. A human murine chimeric EGFR-targeted monoclonal antibody called cetuximab has higher specificity for the extracellular domain of human EGFR and inhibits epidermal growth factor signalling in cells by delaying usual receptor function [19–21]. The US Food and Drug Administration approved preclinical treatments using cetuximab for EGFR-expressing cancer tumours, neck, and head carcinomas, and colorectal carcinomas. This C225 antibody might be a suitable objective for modifying the structure of nanocarriers to improve the therapeutic outcome in ATCs. Remarkably, some researchers have revealed that for a wide spectrum of cancers, the blend of C225 with CPT-11 equivalents such as Au-PFH-NAs has significant synergetic antitumour effects [22–25]. Hence, Au-PFH-NAs in combination with C225 could also enhance ATC diagnostics. However, owing to the reduced vascular dispersal of C225 and the hydrophobicity of Au-PFH-NAs, the NAs penetration of the growth and their quantity in the tumour area were inherently imperfect, showing greatly debilitated anticancer efficacy. In contrast, these problems can be minimized by incorporating Au-PFH-NAs and C225 into one nanotransporter to attain a combination chemotherapy while simultaneously providing targeting capability to the nanocarriers [26–29].
Improved anti-cancer effect of epidermal growth factor-gold nanoparticle conjugates by protein orientation through site-specific mutagenesis
Published in Science and Technology of Advanced Materials, 2021
Nowadays, cancer is still one of the leading causes of death in the world [1]. Treatment of cancer by chemotherapy, surgery, and radiation therapy has been proven to be effective in treating many cells. However, most of them are accompanied with harmful side effects to normal cells, therefore the development of new therapeutic methods is urgently needed [2–4]. The nanomedicine, including nanoparticle-based and two-dimensional (2D) nanoarchitecture-based vehicles, which carrying chemical drugs or protein/peptide drugs are promising to be the new generation medicines due to the improved capacity of the drug-loading, efficacy of cell uptake, and biocompatibility [5–8]. However, the specify of them still needs to be enhanced to selectively kill tumor cells and reduce cytotoxic effects to the normal cells. Recently, the epidermal growth factor receptor (EGFR)-targeted cancer therapeutics has been developed due to the overexpression of EGFR in many tumors [9]. The EGFR is the membrane receptor and plays an important role in cell growth and proliferation [10]. Abnormally activated EGFR by receptor overexpression, mutation, and ligand-independent activation can result in the development of cancer [11]. Therefore, specific EGFR inhibition is one of the promising methods for cancer therapy. There are two major approaches of EGFR inhibition with different mechanism by using monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs). The mAbs (cetuximab, panitumumab) against EGFR are designed specifically to recognize extracellular domain of EGFR to compete with endogenous ligands of EGFR, leading to the inhibition of activation of the EGFR tyrosine kinase induced by the ligand [11–14]. The TKIs such as gefitinib, erlotinib, and canertinib, are small molecules which bind to the intracellular catalytic domain of EGFR tyrosine kinase to compete with adenosine-5ʹ-triphosphate (ATP), inhibiting autophosphorylation and activation of downstream signaling [11,12,15]. Both strategies of inhibition of EGFR have been approved for clinical use and have effective anti-cancer activity. In spite of the effective treatment, it is still difficult to completely cure patients due to the developed resistance of tumor to the EGFR inhibitors. Therefore, the development of new anti-EGFR drugs based on different approaches are expected. Recently, it has been identified that the conjugation of epidermal growth factor (EGF) to gold nanoparticles (GNPs) can gain an enhanced apoptotic efficiency in cancer cells [16,17]. Our group has identified that the emergent unique apoptosis activities of the EGF-GNP conjugates were attributed to the confinements of EGFR within lipid rafts and selective activation of extracellular signal-regulated kinase (ERK) [18]. The EGF conjugates is promising due to the alternative apoptosis pathway of EGFR to overcome the limitation of resistance of inhibitors, and it allows precise delivery of the therapeutics to the intended cell targets which overexpressed EGFR.