Abstract
Simple SummaryAlthough various malignant tumors express high levels of lysyl oxidase (LOX) and though its role in tumor progression is well-defined, there is a lack of sensing techniques to target LOX. This study highlights the application of peptide-functionalized gold nanoprobes for sensing the LOX levels in tumor microenvironments. The gold nanoparticles (AuNPs) in these nanoprobes aggregate upon exposure to LOX, resulting in a red shift of the surface plasmon resonance peak, accompanied by a characteristic color change. This colorimetric assay based on peptide-functionalized AuNP sensitively detects LOX secreted from various cancer cells not only in vitro but also in the tissue extract. In this study, the suggested analytical approach demonstrated high specificity to LOX and did not show any color change in the presence of other enzymes.High LOX levels in the tumor microenvironment causes the cross-linking of extracellular matrix components and increases the stiffness of tumor tissue. Thus, LOX plays an important role in tumorigenesis and in lowering the tumor response to anticancer drugs. Despite comprehensive efforts to identify the roles of LOX in the tumor microenvironment, sensitive and accurate detection methods have not yet been established. Here, we suggest the use of gold nanoparticles functionalized with LOX-sensitive peptides (LS-AuNPs) that aggregate upon exposure to LOX, resulting in a visual color change. LOX-sensitive peptides (LS-peptides) contain lysine residues that are converted to allysine in the presence of LOX, which is highly reactive and binds to adjacent allysine, resulting in the aggregation of the AuNPs. We demonstrated that the synthesized LS-AuNPs are capable of detecting LOX sensitively, specifically both in vitro and in the tissue extract. Moreover, the suggested LS-AuNP-based assay is more sensitive than commonly employed assays or commercially available kits. Therefore, the LS-AuNPs developed in this study can be used to detect LOX levels and can be further used to predict the stiffness or the anticancer drug resistance of the tumor.
Highlights
The extracellular matrix (ECM) is a highly dynamic complex that continuously undergoes the deposition, degradation, and remodeling [1]
AuNPs functionalized with Lysyl oxidase (LOX)-sensitive hexapeptides were introduced to detect LOX levels as a colorimetric sensor in vitro as well as in tumor tissue extracts
We demonstrated that LS-AuNPs are capable of the sensitive detection of LOX after the direct addition of LOX and in cancer cells with different levels of LOX secretion
Summary
The extracellular matrix (ECM) is a highly dynamic complex that continuously undergoes the deposition, degradation, and remodeling [1]. The ECM comprises a diverse group of macromolecules, such as collagen, elastin, proteoglycans, non-collagenous glycoproteins, and elastic fibers [2]. Tumors dysregulate and leverage ECM remodeling, which promotes tumorigenesis and metastasis [5]. The tumor stroma is characterized by the remodeling and stiffening of the ECM [6,7,8]. Abnormal ECM deposition and stiffness are observed during the development of cancer [9]. The cross-linking of collagen and ECM stiffening accompanies tumor progression [6]. During the intramolecular or intermolecular cross-linking of collagen, the collagen fibers become increasingly insoluble and show progressive incremental stiffening [11,12]. The stiffness and elasticity of the tumor microenvironment have been shown to play a critical role in tumorigenesis
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