Magnetic Nanoparticle-Mediated Heating for Biomedical Applications.

Magnetic nanoparticles, especially superparamagnetic nanoparticles (SPIONs), have attracted tremendous attention for various biomedical applications. Facile synthesis and functionalization together with easy control of the size and shape of SPIONS to customize their unique properties, have made it possible to develop different types of SPIONs tailored for diverse functions/applications. More recently, considerable attention has been paid to the thermal effect of SPIONs for the treatment of diseases like cancer and for nanowarming of cryopreserved/banked cells, tissues, and organs. In this mini-review, recent advances on the magnetic heating effect of SPIONs for magnetothermal therapy and enhancement of cryopreservation of cells, tissues, and organs, are discussed, together with the non-magnetic heating effect (i.e., high Intensity focused ultrasound or HIFU-activated heating) of SPIONs for cancer therapy. Furthermore, challenges facing the use of magnetic nanoparticles in these biomedical applications are presented.

Plasmon-assisted random lasing from a single-mode fiber tip.

Random lasing occurs as the result of a coherent optical feedback from multiple scattering centers. Here, we demonstrate that plasmonic gold nanostars are efficient light scattering centers, exhibiting strong field enhancement at their nanotips, which assists a very narrow bandwidth and highly amplified coherent random lasing with a low lasing threshold. First, by embedding plasmonic gold nanostars in a rhodamine 6G dye gain medium, we observe a series of very narrow random lasing peaks with full-width at half-maximum ∼ 0.8 nm. In contrast, free rhodamine 6G dye molecules exhibit only a single amplified spontaneous emission peak with a broader linewidth of 6 nm. The lasing threshold for the dye with gold nanostars is two times lower than that for a free dye. Furthermore, by coating the tip of a single-mode optical fiber with gold nanostars, we demonstrate a collection of random lasing signal through the fiber that can be easily guided and analyzed. Time-resolved measurements show a significant increase in the emission rate above the lasing threshold, indicating a stimulated emission process. Our study provides a method for generating random lasing in the nanoscale with low threshold values that can be easily collected and guided, which promise a range of potential applications in remote sensing, information processing, and on-chip coherent light sources.

Dual Imaging Single Vesicle Surface Protein Profiling and Early Cancer Detection.

Single vesicle molecular profiling has the potential to transform cancer detection and monitoring by precisely probing cancer-associated extracellular vesicles (EVs) in the presence of normal EVs in body fluids, but it is challenging due to the small EV size, low abundance of antigens on individual vesicles, and a complex biological matrix. Here, we report a facile dual imaging single vesicle technology (DISVT) for surface protein profiling of individual EVs and quantification of target-specific EV subtypes based on direct molecular capture of EVs from diluted biofluids, dual EV-protein fluorescence-light scattering imaging, and fast image analysis using Bash scripts, Python, and ImageJ. Plasmonic gold nanoparticles (AuNPs) were used to label and detect targeted surface protein markers on individual EVs with dark-field light scattering imaging at the single particle level. Monte Carlo calculations estimated that the AuNPs could detect EVs down to 40 nm in diameter. Using the DISVT, we profiled surface protein markers of interest across individual EVs derived from several breast cancer cell lines, which reflected the parental cells. Studies with plasma EVs from healthy donors and breast cancer patients revealed that the DISVT, but not the traditional bulk enzyme-linked immunosorbent assay, detected human epidermal growth factor receptor 2 (HER2)-positive breast cancer at an early stage. The DISVT also precisely differentiated HER2-positive breast cancer from HER2-negative breast cancer. We additionally showed that the amount of tumor-associated EVs was tripled in locally advanced patients compared to that in early-stage patients. These studies suggest that single EV surface protein profiling with DISVT can provide a facile and high-sensitivity method for early cancer detection and quantitative monitoring.

Recent Advancements in Mitochondria-Targeted Nanoparticle Drug Delivery for Cancer Therapy.

Mitochondria are critical subcellular organelles that produce most of the adenosine triphosphate (ATP) as the energy source for most eukaryotic cells. Moreover, recent findings show that mitochondria are not only the "powerhouse" inside cells, but also excellent targets for inducing cell death via apoptosis that is mitochondria-centered. For several decades, cancer nanotherapeutics have been designed to specifically target mitochondria with several targeting moieties, and cause mitochondrial dysfunction via photodynamic, photothermal, or/and chemo therapies. These strategies have been shown to augment the killing of cancer cells in a tumor while reducing damage to its surrounding healthy tissues. Furthermore, mitochondria-targeting nanotechnologies have been demonstrated to be highly efficacious compared to non-mitochondria-targeting platforms both in vitro and in vivo for cancer therapies. Moreover, mitochondria-targeting nanotechnologies have been intelligently designed and tailored to the hypoxic and slightly acidic tumor microenvironment for improved cancer therapies. Collectively, mitochondria-targeting may be a promising strategy for the engineering of nanoparticles for drug delivery to combat cancer.

Immunomagnetic Capture and Multiplexed Surface Marker Detection of Circulating Tumor Cells with Magnetic Multicolor Surface-Enhanced Raman Scattering Nanotags.

Circulating tumor cells (CTCs) have substantial clinical implications in cancer diagnosis and monitoring. Although significant progress has been made in developing technologies for CTC detection and counting, the ability to quantitatively detect multiple surface protein markers on individual tumor cells remains very limited. In this work, we report a multiplexed method that uses magnetic multicolor surface-enhanced Raman scattering (SERS) nanotags in conjunction with a chip-based immunomagnetic separation to quantitatively and simultaneously detect four surface protein markers on individual tumor cells in whole blood. Four-color SERS nanotags were prepared using magnetic-optical iron oxide-gold core-shell nanoparticles with different Raman reporters to recognize four different cancer markers with respective antibodies. A microfluidic device was fabricated to magnetically capture the nanoparticle-bound tumor cells and to perform online negative staining and single-cell optical detection. The level of each targeted protein was obtained by signal deconvolution of the mixed SERS signals from individual tumor cells using the classic least squares regression method. The method was tested with spiked tumor cells in human whole blood with three different breast cancer cell lines and compared with the results of purified cancer cells suspended in a phosphate buffer solution. The method, with either spiked cancer cells in blood or purified cancer cells, showed a strong correlation with purified cancer cells by enzyme-linked immunosorbent assay, suggesting the potential of our method for the reliable detection of multiple surface markers on CTCs. Combining immunomagnetic enrichment with high specificity, multiplexed targeting for the capture of CTC subpopulations, multicolor SERS detection with high sensitivity and specificity, microfluidics for handling rare cells and magnetic-plasmonic nanoparticles for dual enrichment and detection, our method provides an integrated, yet a simple and an efficient platform that has the potential to more sensitively detect and monitor cancer metastasis.

Small mode volume plasmonic film-coupled nanostar resonators.

Confining and controlling light in extreme subwavelength scales are tantalizing tasks. In this work, we report a study of individual plasmonic film-coupled nanostar resonators where polarized plasmonic optical modes are trapped in ultrasmall volumes. Individual gold nanostars, separated from a flat gold film by a thin dielectric spacer layer, exhibit a strong light confinement between the sub-10 nm volume of the nanostar's tips and the film. Through dark field scattering measurements of many individual nanostars, a statistical observation of the scattered spectra is obtained and compared with extensive simulation data to reveal the origins of the resonant peaks. We observe that an individual nanostar on a flat gold film can result in a resonant spectrum with single, double or multiple peaks. Further, these resonant peaks are strongly polarized under white light illumination. Our simulation data revealed that the resonant spectrum of an individual film-coupled nanostar resonator is related to the symmetry of the nanostar, as well as the orientation of the nanostar relative to its placement on the gold substrate. Our results demonstrate a simple new method to create an ultrasmall mode volume and polarization sensitive plasmonic platform which could be useful for applications in sensing or enhanced light-matter interactions.

Molecular Detection and Analysis of Exosomes Using Surface-Enhanced Raman Scattering Gold Nanorods and a Miniaturized Device.

Exosomes are a potential source of cancer biomarkers. Probing tumor-derived exosomes can offer a potential non-invasive way to diagnose cancer, assess cancer progression, and monitor treatment responses. Novel molecular methods would facilitate exosome analysis and accelerate basic and clinical exosome research. Methods: A standard gold-coated glass microscopy slide was used to develop a miniaturized affinity-based device to capture exosomes in a target-specific manner with the assistance of low-cost 3-D printing technology. Gold nanorods coated with QSY21 Raman reporters were used as the label agent to quantitatively detect the target proteins based on surface enhanced Raman scattering spectroscopy. The expressions of several surface protein markers on exosomes from conditioned culture media of breast cancer cells and from HER2-positive breast cancer patients were quantitatively measured. The data was statistically analyzed and compared with healthy controls. Results: A miniaturized 17 × 5 Au array device with 2-mm well size was fabricated to capture exosomes in a target-specific manner and detect the target proteins on exosomes with surface enhanced Raman scattering gold nanorods. This assay can specifically detect exosomes with a limit of detection of 2×106 exosomes/mL and analyze over 80 purified samples on a single device within 2 h. Using the assay, we have showed that exosomes derived from MDA-MB-231, MDA-MB-468, and SKBR3 breast cancer cells give distinct protein profiles compared to exosomes derived from MCF12A normal breast cells. We have also showed that exosomes in the plasma from HER2-positive breast cancer patients exhibit significantly (P ≤ 0.01) higher level of HER2 and EpCAM than those from healthy donors. Conclusion: We have developed a simple, inexpensive, highly efficient, and portable Raman exosome assay for detection and protein profiling of exosomes. Using the assay and model exosomes from breast cancer cells, we have showed that exosomes exhibit diagnostic surface protein markers, reflecting the protein profile of their donor cells. Through proof-of-concept studies, we have identified HER2 and EpCAM biomarkers on exosomes in plasma from HER2-positive breast cancer patients, suggesting the diagnostic potential of these markers for breast cancer diagnostics. This assay would accelerate exosome research and pave a way to the development of novel cancer liquid biopsy for cancer detection and monitoring.

Gold Nanoparticle Based Platforms for Circulating Cancer Marker Detection.

Detection of cancer-related circulating biomarkers in body fluids has become a cutting-edge technology that has the potential to noninvasively screen cancer, diagnose cancer at early stage, monitor tumor progression, and evaluate therapy responses. Traditional molecular and cellular detection methods are either insensitive for early cancer intervention or technically costly and complicated making them impractical for typical clinical settings. Due to their exceptional structural and functional properties that are not available from bulk materials or discrete molecules, nanotechnology is opening new horizons for low cost, rapid, highly sensitive, and highly specific detection of circulating cancer markers. Gold nanoparticles have emerged as a unique nanoplatform for circulating biomarker detection owning to their advantages of easy synthesis, facile surface chemistry, excellent biocompatibility, and remarkable structure and environment sensitive optical properties. In this review, we introduce current gold nanoparticle-based technology platforms for the detection of four major classes of circulating cancer markers - circulating tumor cells, vesicles, nucleic acids, and proteins. The techniques will be summarized in terms of signal detection strategies. Distinctive examples are provided to highlight the state-of-the-art technologies that significantly advance basic and clinical cancer research.

Synthesis and Properties of Magnetic-Optical Core-Shell Nanoparticles.

Due to their high integrity, facile surface chemistry, excellent stability, and dual properties from the core and shell materials, magnetic-plasmonic core-shell nanoparticles are of great interest across a number of science, engineering and biomedical disciplines. They are promising for applications in a broad range of areas including catalysis, energy conversion, biological separation, medical imaging, disease detection and treatment. The technological applications have driven the need for high quality nanoparticles with well controlled magnetic and optical properties. Tremendous progress has been made during past few decades in synthesizing and characterizing magnetic-plasmonic core-shell nanoparticles, mainly iron oxide-gold core-shell nanoparticles. This review introduces various approaches for the synthesis of spherical and anisotropic magnetic-plasmonic core-shell nanoparticles focusing on iron oxide-gold core-shell nanoparticles. Growth mechanisms are discussed to provide understanding of the key factors controlling shape-controlled synthesis. Magnetic and optical properties are summarized from both computational and experimental studies.

Size- and Shape-Controlled Synthesis and Properties of Magnetic-Plasmonic Core-Shell Nanoparticles.

Magnetic-plasmonic core-shell nanomaterials offer a wide range of applications across science, engineering and biomedical disciplines. However, the ability to synthesize and understand magnetic-plasmonic core-shell nanoparticles with tunable sizes and shapes remains very limited. This work reports experimental and computational studies on the synthesis and properties of iron oxide-gold core-shell nanoparticles of three different shapes (sphere, popcorn and star) with controllable sizes (70 to 250 nm). The nanoparticles were synthesized via a seed-mediated growth method in which newly formed gold atoms were added onto gold-seeded iron oxide octahedrons to form gold shell. The evolution of the shell into different shapes was found to occur after the coalescence of gold seeds, which was achieved by controlling the amount of additive (silver nitrate) and reducing agent (ascorbic acid) in the growth solution. First principles calculation, together with experimental results, elucidated the intimate roles of thermodynamic and kinetic parameters in the shape-controlled synthesis. Both discrete dipole approximation calculation and experimental results showed that the nanopopcorns and nanostars exhibited red-shifted plasmon resonance compared with the nanospheres, with the nanostars giving multispectral feature. This research has made a great step further in manipulating and understanding magnetic-plasmonic hybrid nanostructures and will make important impact in many different fields.