Stimuli-Responsive Nanodiamond-Based Biosensor for Enhanced Metastatic Tumor Site Detection

Abstract

Metastasis is often critical to cancer progression and linked to poor survival and drug resistance. Early detection of metastasis, as well as identification of metastatic tumor sites, can improve cancer patient survival. Thus, developing technology to improve the detection of cancer metastasis biomarkers can improve both diagnosis and treatment. In this study, we investigated the use of nanodiamonds to develop a stimuli-responsive metastasis detection complex that utilizes matrix metalloproteinase 9 (MMP9) as a metastasis biomarker, as MMP9 increased expression has been shown to be indicative of metastasis. The nanodiamond-MMP9 biosensor complex consists of nanodiamonds functionalized with MMP9-specific fluorescent-labeled substrate peptides. Using this design, protease activity of MMP9 can be accurately measured and correlated to MMP9 expression. The nanodiamond-MMP9 biosensor also demonstrated an enhanced ability to protect the base sensor peptide from nonspecific serum protease cleavage. This enhanced peptide stability, combined with a quantitative stimuli-responsive output function, provides strong evidence for the further development of a nanodiamond-MMP9 biosensor for metastasis site detection. More importantly, this work provides the foundation for use of nanodiamonds as a platform for stimuli-responsive biosensors and theranostic complexes that can be implemented across a wide range of biomedical applications.

Matrix Metalloproteinase-9 (MMP-9) as a Cancer Biomarker and MMP-9 Biosensors: Recent Advances

“…Another study developed a nanodiamond-based MMP-9 biosensor [ 123 ]. In this biosensor, a fluorescent-labeled peptide with MMP-9 cleavage site is bonded to nanodiamond.…”

Carbon Nanomaterials as Versatile Platforms for Biosensing Applications

“…Energy transfer between FITC and 5-TAMRA occurred when the peptide was uncleaved, resulting in fluorescence quenching of the FITC molecule. Meanwhile, the FITC emission signal was measured, which indicated no energy transfer to 5-TAMRA when MMP9 cleaved the peptide, although the distance between FITC and 5-TAMRA increased [ 51 ].…”

Clinical Applications of Carbon Nanomaterials in Diagnostics and Therapy

“…Inherent fluorescence of FNDs has also been explored as alternative options primarily for biomedical imaging and diagnostic applications, but also has potential as a platform for drug delivery . For both DNDs and FNDs, the advantages of nanodiamonds toward both drug delivery and imaging also support potential of applying NDs toward the emerging fields of theranostics and stimuli‐responsive drug delivery and imaging . Whether used alone as a platform for drug delivery or in combination with other materials, NDs are poised to transform medicine.…”

“…The tunability of functional groups on NDs as well as inherent fluorescent properties of FNDs makes NDs an attractive platform for developing biomedical imaging tools and clinical diagnostics . While the use of fluorescence signals can be quickly translated toward biomedical research applications, the unique electrostatic surface potential properties of NDs confer the ability to develop enhanced ND‐based magnetic resonance (MR) imaging contrast agents that can provide greater imaging sensitivity at lower dosages compared to conventional contrast agents .…”