nanotechnology and detection and early detection of cancer (2023)

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Current imaging techniques can only detect cancer after causing a visible change in a tissue, by which time thousands of cells have proliferated and perhaps metastasized. And even if it is visible, the type of tumor - malignant or benign - and the characteristics that might make it responsive to a particular treatment need to be evaluated through tissue biopsies. Although some primary malignancies can be determined as metastatic, tumors arising from metastatic sites and micrometastases are extremely difficult to detect with modern imaging techniques, despite the known tissues in which they commonly occur.First. Finally, surgical resection of tumor tissue remains the standard of care for many types of tumors, and surgeons must weigh the consequences of removing healthy, often vital, tissue versus the unevenly grown cancerous mass. Ultimately, with current surgical techniques, it is not possible to remove cancer cells at the single cell level.

Nanotechnology-based imaging contrast agents being developed and implemented today offer the opportunity to target and significantly improve in vivo tumor detection by traditional scanning devices such as magnetic resonance imaging (MRI) (PET) and computed tomography (CT). ). In addition, current nanoscale imaging platforms enable new non-traditional imaging modalities used for clinical cancer treatment and diagnosis, e.g. B. photoacoustic tomography (PAT), Raman spectroscopic imaging and multimodal imaging (i.e. specific contrast agents for several imaging modalities simultaneously). ). Nanotechnology enables all of these platforms through their ability to deliver multiple components simultaneously (e.g., cancer cell-specific targeting agents or traditional imaging contrast agents) and nanoscale materials, which are the very contrast agents that enable signal.

NCI-funded research has produced many notable examples in recent years. For example, researchers at Stanford University and Memorial Sloan Kettering Cancer Center have developed multimodal nanoparticles capable of delineating the edges of brain tumors preoperatively and intraoperatively. These MRI-PAT Raman nanoparticles can be used for both tumor growth tracking and surgical staging by MRI, but also in the same particle used during surgical resection of the brain tumor to give the surgeon "eyes" down to the individual at the cancer cell level, increasing the potential for tumor-specific tissue removal.

For metastatic melanoma, researchers at MSKCC and Cornell University have developed hybrid silica nanoparticles ('C-dots') that offer optical contrast and PET image contrast on the same platform. These nanoparticles actively target cancer with cRGDY peptides that target this specific tumor type and have done so successfully in early clinical trials.

Another clinical cancer imaging problem addressed by nanoscale solutions is prostate cancer. Stanford University researchers have recently developed nanotechnologies that provide the anatomical size and location of prostate cancer cells (nanobubbles for ultrasound imaging) and functional information to prevent overdiagnosis/treatment and monitor progress (self-assembling nanoparticles for photoacoustic imaging). The nanoplatforms developed by this group are directly coupled to their recently approved handheld transrectal photoacoustic ultrasound (TUSPA) device. Ultimately, it offers a more effective, integrated and less invasive prostate cancer imaging and biopsy technique for diagnosis and prognosis prior to performing common procedures (surgical resection, radiation therapy, etc.).

Similarly, gold nanoparticles are used to improve light scattering for endoscopic techniques that can be used during colonoscopy. A really powerful potential that has always been envisioned for nanotechnology in cancer has been the potential to simultaneously image and deliver therapy in vivo, and various groups have been pushing these nanoscale “theranostic” platforms. A group at Emory University developed one for ovarian and pancreatic cancers, which are traditionally more difficult to treat. Its pancreatic cancer platform can destroy the fibrotic stromal tissue that protects these tumors in the pancreas from. After crossing this barrier, they consist of magnetic iron cores that allow MRI contrast for diagnosis and deliver small molecule drugs directly to cancer cells for treatment.

Finally, nanotechnology enables the visualization of molecular markers that identify specific stages and therapy-induced cancer cell death, allowing physicians to see cells and molecules undetectable by traditional imaging. A group at Stanford developed the Target-Enabled in Situ Ligand Assembly (TESLA) nanoparticle system. This is based on nanoparticles that form directly in the body after intravenous injection of molecular precursors. Precursors contain specific sequences of atoms that can only form larger nanoparticles after being cleaved by enzymes produced by cancer cells during apoptosis (i.e. cell death) and carry various imaging contrast agents to monitor the local tumor response (PET , MRI etc.). to therapies. The ability to follow cancer cell death in vivo and at the molecular level is extremely important to provide effective dosing regimens and/or to accurately administer new therapies or combinations.

In vitro detection

activated for nanotechnologyIn-vitro-Diagnosticsoffer high sensitivity and selectivity, as well as the ability to perform simultaneous measurements on multiple targets. Well-established manufacturing techniques (e.g., lithography) can be used to create integrated handheld devices or point-of-care systems. A diagnostic device or biosensor contains a biological recognition element that can detect the presence, activity, or concentration of a specific biological molecule in solution through a biochemical reaction. This reaction may involve, for example: antigen and antibody binding, hybridization of two single-stranded DNA fragments, or capture ligand binding to the cell surface epitope. A transducer portion of the sensor device is used to convert the biochemical event into a quantifiable signal that can be measured. Transmission mechanisms can be based on light, magnetic or electronic effects.

Various devices have been developed for the detection of various serum or tissue biological signatures. Some examples of nanotechnology or nanoparticle based diagnostic devices are shown in Figure #. The barcode bioassay was developed as a sandwich immunoassay in the laboratory of Chad Mirkin at Northwestern University. It uses magnetic nanoparticles (MMPs) functionalized with monoclonal antibodies specific to the target protein of interest, which are then mixed with the sample to promote target protein capture. The hybrid MMP-protein structures are then combined with gold nanoparticle (Au-NP) probes bearing DNA barcodes. Target protein-specific DNA barcodes are released into solution and detected using the scanometric assay with sensitivities in the femtopicomolar range.

James Heath's lab at Caltech has developed sandwich immunoassay devices based on DNA-encoded antibody libraries (DEAL). The DEAL technique uses DNA-directed immobilization of antibodies in microfluidic channels, allowing a pre-patterned single-stranded (ss) DNA barcode microarray to be converted into an antibody microarray. The ssDNA oligomers attached to the sensor surface are robust and can withstand high channel fabrication temperatures. Subsequent flow of the DNA-antibody conjugates into the channels converts the DNA microarray into an antibody microarray and allows the performance of surface-binding multiplex sandwich immunoassays. These devices enable on-chip blood separation and measurement of large amounts of protein directly from blood.

The diagnostic magnetic resonance imaging (DMR) sensor platform was developed in Ralph Weissleder's laboratory at Massachusetts General Hospital. The DMR mechanism uses changes in the transverse relaxation signal of water molecules in a magnetic field as a detection mechanism for analytes labeled with magnetic nanoparticles. Highly integrated systems, including microfluidic processing circuits and high signal-to-noise ratio nuclear magnetic resonance (NMR) acquisition heads, have been built and are capable of detecting the presence of cells, vesicles and proteins in clinical samples.

Shan Wang's lab at Stanford University has developed giant magnetoresistive (GMR) biosensors for protein detection. These nanosensors work by changing their electrical resistance in response to changes in the local magnetic field. They were adapted to detect biological signatures in solution and implemented a traditional sandwich assay directly on GMR nanosensors. Antibodies are immobilized on the surface of the GMR sensor and serve as capture probes for the sample containing target proteins. A magnetic particle is used to tag the biomolecule of interest in the sample and the GMR sensor is used for signal transmission. These sensors have been used to measure protein concentrations in complex sample mixtures and have also been used to assess the kinetics of protein interactions.

The devices described above are capable of analyzing large panels of biological signatures while providing a high level of multiplexing. Data analysis can establish correlations between different levels of biomarkers and map signal correlations of networks, thus providing tools for patient stratification based on their response to different treatments and ultimately improving the therapeutic efficacy of the selected treatment. Recent advances in microfluidic technologies have opened up opportunities to integrate sample preparation and processing with biosensors, creating fully integrated devices that provide complete data from a single sample directly for medical diagnosis.

Measurement of response to therapy and liquid biopsy

Measuring an individual patient's response to therapy over the course of their illness is the basis for accurate medical care and prognosis. Accurate and relevant disease monitoring can enable optimized treatment regimens (e.g., correction of therapeutic course, drug combinations, and dose reduction), preventive clinical decision-making (e.g., therapeutic responders versus non-responders and more), and patient-to-clinic stratification of trials. In addition to the more traditional gold standards of in vivo imaging, tissue biopsy, and in vitro diagnostics available for this purpose, "liquid biopsy" offers the ability to measure response to therapy through single and serial blood draws. Conventional biopsies involve the direct resection of small tumor tissue volumes and therefore remain invasive procedures that cannot provide the sample collection necessary to follow the course of the disease in relation to the course of therapy or the dynamics of its evolving biology. Liquid biopsies rely on the fact that tumors release material (eg, cells, DNA, other cancer-specific biomolecules) into the circulation over time and in response to therapy. Although the amount of materials eliminated from a given tumor and/or stage is typically at incredibly low concentrations compared to the rest of the blood components (e.g. erythrocytes, leukocytes, platelets, plasma, etc.). This requires specific and sensitive tools to detect, capture and purify circulating tumor material from the rest. Nanotechnology is making it possible for these tools to become a reality.

Recent technological advances in coupling complex microfluidics and nanoscale materials have enabled high-purity detection and downstream functional characterization of circulating tumor cells (CTCs), cell-free tumor DNA, microemboli, exosomes, proteins, neoantigens, and more. Recent examples include the capture and subsequent release of CTCs in microfluidic systems to keep cells viable for downstream whole genome sequencing, ex vivo expansion, RNA sequencing, and more. Of these examples, one type of device uses magnetic nanoparticles to enrich whole blood prior to magnetic separation within the microfluidic, and the other device uses thermoresponsive nanopolymers that specifically capture CTCs as they flow through the microfluidic, and then are released once again after a temperature change blood is present processing is complete. In both cases the detection sensitivities are very high (e.g. for enumeration > 95%) and the detection purity is much higher than other non-nanomaterials based devices. In addition, processing times are increasing each year as technology advances, currently averaging 10 mL of blood per 30 minutes.