Optomechanical devices for deep plasma cancer proteomics

Abstract

Most of the cancer deaths could be avoided by early detection of the tumor when it is confined to its primary site and it has not metastasized. To this aim, one of the most promising strategies is the discovery and detection of protein biomarkers shed by the young tumor to the bloodstream. Proteomic technologies, mainly mass spectrometry and multiplexed immunoassays, have rapidly developed during last years with improved limits of detection and multiplexing capability. Unfortunately, these developments together major investments and large international efforts have not resulted into new useful protein biomarkers. Here, we analyze the potential and limitations of current proteomic technologies for detecting protein biomarkers released into circulation by the tumor. We find that these technologies can hardly probe the deepest region of the plasma proteome, at concentrations below the pg/mL level, where protein biomarkers for early cancer detection may exist. This clearly indicates the need of incorporating novel ultrasensitive techniques to the proteomic tool-box that can cover the inaccessible regions of the plasma proteome. We here propose biological detectors based on nanomechanical systems for discovery and detection of cancer protein biomarkers in plasma. We review the modes of operation of these devices, putting our focus on recent developments on nanomechanical sandwich immunoassays and nanomechanical spectrometry. The first technique enables reproducible immunodetection of proteins at concentrations well below the pg/mL level, with a limit of detection on the verge of 10 ag/mL. This technology can potentially detect low abundance tumor-associated proteins in plasma at the very early stages of the tumor. The second technique enables the identification of individual intact proteins by two physical coordinates, the mass and stiffness, instead of the mass-to-charge ratio of the protein constituents. This technology enormously simplifies the identification of proteins and it can provide useful information on interactions and posttranslational modifications, that otherwise is lost in mass spectrometry.

Optomechanical detection of vibration modes of a single bacterium

“…We note that micro-and nanomechanical resonators have been previously used for measuring the mass of single biological particles 21,22,23 . In addition to the mass, the stiffness of biological particles has been measured with compliant mechanical structures such as microcantilevers 13,24 . The added mass induces a downshift of the resonance frequency of the nanomechanical resonator, whereas the stiffness of the particle induces a upshift, usually smaller that the mass effect.…”

Large-scale parallelization of nanomechanical mass spectrometry with weakly-coupled resonators

“…This extreme sensitivity has led to the development of nanomechanical mass spectrometry using resonant sensors with applications in the detection of nanoparticles and in proteomics 10–12 . New theoretical methodologies have also been developed to extract—from the adsorption-induced multi-mode eigenfrequency variation—an inertial imaging of soft/compliant adsorbates 13,14 , or the mass, position and stiffness of hard/non-compliant analytes 15,16 . In contrast to their extreme mass sensitivity, miniaturization simultaneously reduces the capture cross-section of these resonant sensors and necessitates the use of more advanced detection systems, which can hinder implementation in a practical setting 1,12 .…”

Personalized Medicine for Antibiotics: The Role of Nanobiosensors in Therapeutic Drug Monitoring

“…The interaction between the analyte and the ligand induces a differential change in the surface tension of the liquid, which generates a change in deflection and/or in the resonance frequency [ 275 ]. Nanomechanical biosensors have been used in different areas, mainly in the identification of pathogens in human samples [ 305 ] and for the identification of proteins, such as topoisomerases or cancer marker proteins [ 306 , 307 , 308 , 309 , 310 ]. However, there is no evidence that this type of device was applied to the detection or quantification of antibiotics in samples of body fluids.…”