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Biophysical and Biochemical Characterization of Peptide, Protein, and Bioconjugate Products
Published in Sandeep Nema, John D. Ludwig, Parenteral Medications, 2019
Tapan K. Das, James A. Carroll
A typical approach for the determination of disulfides in a protein involves proteolytic mapping under nonreducing conditions, followed by detection of the resulting disulfide-bound peptides formed, often using mass spectrometry [54–56]. For small proteins with few cysteines, this may be straightforward. For larger proteins with many cysteine residues, the complexity may require additional analyses to map all the disulfides. A parallel analysis, in which all the disulfides are reduced, with a comparison of which peaks have changed upon reduction, can aid in the detection of peptides involved in disulfide bonding. IgG molecules, which are a major class of biotherapeutics in the form of monoclonal antibodies (mAbs), have several disulfides predicted in the constant and variable regions of the molecule. These disulfides serve to connect the heavy and light chains together and to form the intrachain loops necessary for the IgG to maintain its functions. Most of the commercial therapeutic mAbs are IgG1 molecules, which is the major subclass of the IgG class of molecules. The disulfide bonding of IgG1 molecules has been well-established. IgG2 molecules have been under development as biotherapeutic entities for some indications due to their low level of secondary activity, such as antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. One IgG2 molecule, panitumumab, which is an anti-epidermal growth factor receptor mAb, has been approved for use for the treatment of metastatic colorectal carcinoma [57]. IgG2 molecules have an intrinsic heterogeneity in their disulfide connectivity, which leads to a mixture of at least three forms of disulfide isomers [58]. These disulfide-mediated isomers differ in the interchain disulfide bonds. As therapeutic entities, the levels of each form and their impact to safety and efficacy are attributes that may be assessed.
Applications of Silica-Based Nanomaterials for Combinatorial Drug Delivery in Breast Cancer Treatment
Published in Yasser Shahzad, Syed A.A. Rizvi, Abid Mehmood Yousaf, Talib Hussain, Drug Delivery Using Nanomaterials, 2022
Mubin Tarannum, Juan L. Vivero-Escoto
Combination therapies for BC are performed by combining alkylating agents, cyclophosphamide, and antimetabolites (methotrexate and 5-FU). Combining multiple chemotherapy agents results in a higher response rate, better efficacy, and dose reduction, reduce drug resistance. One of the first few combination trials includes a phase II neoadjuvant trial, docetaxel plus epirubicin combination was evaluated in advanced stage BC and the trial showed a response rate of 76.7% with the participating drugs (de Matteis et al. 2002). In the study reported by National Surgical Adjuvant Breast and Bowel Project Protocol B-27, docetaxel after doxorubicin (DOX) plus cyclophosphamide resulted in increased pathological response rates for operable BC (Bear et al. 2003). Further, sequencing chemo taxanes prior to anthracyclines could improve the complete response (Earl et al. 2014; von Minckwitz et al. 2012). Docetaxel and carboplatin combination was investigated in stage II or III of BC and showed 16% pCR including patients with TNBC. The study concluded four cycles of neoadjuvant carboplatin and docetaxel given 2 weeks apart, followed by pegfilgrastim (Roy et al. 2013). Similarly, other drugs like DOX, platinum-based drugs (cisplatin and carboplatin) are also included in combinations. These trials support the usage of multidrug chemo agents for improved BC therapy. Taxanes form another important class of chemo agents in BC which include paclitaxel and docetaxel. Paclitaxel has been combined with DOX (L Gianni et al. 1995), cisplatin (Gelmon et al. 1996; Wasserheit et al. 1996), cyclophosphamide, 5-FU, and mitomycin. Chemo agents are also combined with hormonal therapy and molecular agents including panitumumab and lapatinib. EGFR inhibitors including panitumumab were added to various chemo agents with improved outcomes. In addition, heat shock protein (Hsp90) inhibitors were also combined with chemo agents and molecular therapies, specifically, 17-AAG plus trastuzumab showed potent anticancer activity in metastatic BC (Lu et al. 2012; Modi et al. 2011).
An update on locoregional percutaneous treatment technologies in colorectal cancer liver metastatic disease
Published in Expert Review of Medical Devices, 2023
Stavros Spiliopoulos, Ornella Moschovaki-Zeiger, Akshay Sethi, George Festas, Lazaros Reppas, Dimitris Filippiadis, Nikolaos Kelekis
A limitation of this RCT was the lack of bevacizumab, oxaliplatin, cetuximab, or panitumumab in the study as this was not part of standard care at the time; however, studies have shown better overall survival when used along with FOLFIRI [23].
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.