Dual‐Modality Surface‐Enhanced Resonance Raman Scattering and Multispectral Optoacoustic Tomography Nanoparticle Approach for Brain Tumor Delineation

Difficulty in visualizing glioma margins intraoperatively remains a major issue in the achievement of gross total tumor resection and, thus, better clinical outcome of glioblastoma (GBM) patients. Here, the potential of a new combined optical + optoacoustic imaging method for intraoperative brain tumor delineation is investigated. A strategy using a newly developed gold nanostar synthesis method, Raman reporter chemistry, and silication method to produce dual‐modality contrast agents for combined surface‐enhanced resonance Raman scattering (SERRS) and multispectral optoacoustic tomography (MSOT) imaging is devised. Following intravenous injection of the SERRS‐MSOT‐nanostars in brain tumor bearing mice, sequential MSOT imaging is performed in vivo and followed by Raman imaging. MSOT is able to accurately depict GBMs three‐dimensionally with high specificity. The MSOT signal is found to correlate well with the SERRS images. Because SERRS enables uniquely sensitive high‐resolution surface detection, it could represent an ideal complementary imaging modality to MSOT, which enables real‐time, deep tissue imaging in 3D. This dual‐modality SERRS‐MSOT‐nanostar contrast agent reported here is shown to enable high precision depiction of the extent of infiltrating GBMs by Raman‐ and MSOT imaging in a clinically relevant murine GBM model and could pave new ways for improved image‐guided resection of brain tumors.     

High Surface‐Enhanced Raman Scattering Performance of Individual Gold Nanoflowers and Their Application in Live Cell Imaging

Molecular imaging techniques based on surface‐enhanced Raman scattering (SERS) face a lack of reproducibility and reliability, thus hampering its practical application. Flower‐like gold nanoparticles have strong SERS enhancement performance due to having plenty of hot‐spots on their surfaces, and this enhancement is not dependent on the aggregation of the particles. These features make this kind of particle an ideal SERS substrate to improve the reproducibility in SERS imaging. Here, the SERS properties of individual flower‐like gold nanoparticles are systematically investigated. The measurements reveal that the enhancement of a single gold nanoparticle is independent of the polarization of the excitation laser with an enhancement factor as high as 10⁸. After capping with Raman signal molecules and folic acid, the gold nanoflowers show strong Raman signal in the living cells, excellent targeting properties, and a high signal‐to‐noise ratio for SERS imaging.     

磁性氧化铁高效磁共振造影剂的制备及应用

采用高温热分解法, 以乙酰丙酮铁为铁源, 生物相容性良好的聚乙二醇(PEG1000)作为溶剂、还原剂及修饰剂制备PEG修饰的氧化铁纳米粒子(PEG-SPIONs), 并研究其在小鼠体内的造影效果。X射线衍射(XRD)分析表明样品中含有Fe₃O₄晶相。透射电镜(TEM)结果显示, 合成的PEG-SPIONs形貌均一, 主要为等轴晶形, 纳米粒度及电位分析表明其表面呈负电性, 分散在水中的动力学粒径为20 nm。磁性能结果表明合成的PEG-SPIONs室温下具有超顺磁性, 并且具有较高的r₂/r₁值。细胞活性研究表明PEG-SPIONs具有较低的生物毒性, 体内的磁共振成像结果显示出PEG-SPIONs优异的对比增强效果, 说明PEG-SPIONs可以作为高效的T₂磁共振成像造影剂。     

Raman Imaging from Microscopy to Nanoscopy,and to Macroscopy

Raman spectroscopy can not only provide intrinsic fingerprint information about a sample, but also utilize the merits of the narrow bandwidth and low background of Raman spectra, offering itself as a promising multiplex analytical technique. Raman microscopy has become particularly attractive recently because it has demonstrated itself as an important imaging technique for various samples, from biological samples and chemical systems to industrially important silicon‐based wafers. In this Concept article, some of the most recent advances in Raman imaging techniques are critically reviewed, and the advantages and problems associated with the current techniques are discussed. Particular emphasis is placed on its future directions, from both the technical and application sides.     

Correct Spectral Conversion between Surface‐Enhanced Raman and Plasmon Resonance Scattering from Nanoparticle Dimers for Single‐Molecule Detection

Simultaneous measurement of surface‐enhanced Raman scattering (SERS) and localized surface plasmon resonance (LSPR) in nanoparticle dimers presents outstanding opportunities in molecular identification and in the elucidation of physical properties, such as the size, distance, and deformation of target species. SERS–LSPR instrumentation exists and has been used under limited conditions, but the extraction of SERS and LSPR readouts from a single measurement is still a challenge. Herein, the extraction of LSPR spectra from SERS signals is reported and a tool for measuring the interparticle distance from Raman enhancement data by the standardization of the SERS signal is proposed. The SERS nanoruler mechanism incorporates two important aspects (the LSPR scattering peak shift and the Raman shift for measuring interparticle distance), and signifies their exact one‐to‐one correspondence after spectral correction. The developed methodology is applied to calculate the interparticle distance between nanoparticle dimers from SERS signals, to detect and quantify DNA at the single‐molecule level in a base‐pair‐specific manner. It is also shown that the SERS nanoruler concept can be used in structural analysis for the specific detection of the interaction of immunoglobulin G (IgG) with its target from bianalyte Raman signals with identical shaping at single‐molecule resolution. The SERS profile shaping approach not only offers a new detection mechanism for single molecules, but also has excellent potential for studying protein interactions and the intracellular detection of mRNA.     

Ultrasmall Nanoplatforms as Calcium‐Responsive Contrast Agents for Magnetic Resonance Imaging

The preparation of ultrasmall and rigid platforms (USRPs) that are covalently coupled to macrocycle‐based, calcium‐responsive/smart contrast agents (SCAs), and the initial in vitro and in vivo validation of the resulting nanosized probes (SCA‐USRPs) by means of magnetic resonance imaging (MRI) is reported. The synthetic procedure is robust, allowing preparation of the SCA‐USRPs on a multigram scale. The resulting platforms display the desired MRI activity—i.e., longitudinal relaxivity increases almost twice at 7 T magnetic field strength upon saturation with Ca²⁺. Cell viability is probed with the MTT assay using HEK‐293 cells, which show good tolerance for lower contrast agent concentrations over longer periods of time. On intravenous administration of SCA‐USRPs in living mice, MRI studies indicate their rapid accumulation in the renal pelvis and parenchyma. Importantly, the MRI signal increases in both kidney compartments when CaCl₂ is also administrated. Laser‐induced breakdown spectroscopy experiments confirm accumulation of SCA‐USRPs in the renal cortex. To the best of our knowledge, these are the first studies which demonstrate calcium‐sensitive MRI signal changes in vivo. Continuing contrast agent and MRI protocol optimizations should lead to wider application of these responsive probes and development of superior functional methods for monitoring calcium‐dependent physiological and pathological processes in a dynamic manner.     

Guiding Brain‐Tumor Surgery via Blood–Brain‐Barrier‐Permeable Gold Nanoprobes with Acid‐Triggered MRI/SERRS Signals

Surgical resection is a mainstay in the treatment of malignant brain tumors. Surgeons, however, face great challenges in distinguishing tumor margins due to their infiltrated nature. Here, a pair of gold nanoprobes that enter a brain tumor by crossing the blood–brain barrier is developed. The acidic tumor environment triggers their assembly with the concomitant activation of both magnetic resonance (MR) and surface‐enhanced resonance Raman spectroscopy (SERRS) signals. While the bulky aggregates continuously trap into the tumor interstitium, the intact nanoprobes in normal brain tissue can be transported back into the blood stream in a timely manner. Experimental results show that physiological acidity triggers nanoparticle assembly by forming 3D spherical nanoclusters with remarkable MR and SERRS signal enhancements. The nanoprobes not only preoperatively define orthotopic glioblastoma xenografts by magnetic resonance imaging (MRI) with high sensitivity and durability in vivo, but also intraoperatively guide tumor excision with the assistance of a handheld Raman scanner. Microscopy studies verify the precisely demarcated tumor margin marked by the assembled nanoprobes. Taking advantage of the nanoprobes' rapid excretion rate and the extracellular acidification as a hallmark of solid tumors, these nanoprobes are promising in improving brain‐tumor surgical outcome with high specificity, safety, and universality.     

Superficial‐Layer‐Enhanced Raman Scattering (SLERS) for Depth Detection of Noncontact Molecules

Although the strength of Raman signals can be increased by many orders of magnitude on noble metal nanoparticles, this enhancement is confined to an extremely short distance from the Raman‐active surface. The key to the development of Raman spectroscopy for applications in diagnosis and detection of cancer and inflammatory diseases, and in pharmacology, relies on the capability of detecting analytes that are noninteractive with Raman‐active surfaces. Here, a new Raman enhancement system is constructed, superficial‐layer‐enhanced Raman scattering (SLERS), by covering elongated tetrahexahedral gold nanoparticle arrays with a superficial perovskite (CH₃NH₃PbBr₃) film. Plasmonic decay is depressed along the vertical direction away from the noble metal surface and the penetration depth is increased in the perovskite media. The vertical penetration of SLERS is verified by the spatial distribution of the analytes via Raman imaging in layer‐scanning mode.     

Multifunctional Magnetic Gd3+‐Based Coordination Polymer Nanoparticles: Combination of Magnetic Resonance and Multispectral Optoacoustic Detections for Tumor‐Targeted Imaging in vivo

To overcome traditional barriers in optical imaging and microscopy, optoacoustic‐imaging has been changed to combine the accuracy of spectroscopy with the depth resolution of ultrasound, achieving a novel modality with powerful in vivo imaging. However, magnetic resonance imaging provides better spatial and anatomical resolution. Thus, a single hybrid nanoprobe that allows for simultaneous multimodal imaging is significant not only for cutting edge research in imaging science, but also for accurate clinical diagnosis. A core‐shell‐structured coordination polymer composite microsphere has been designed for in vivo multimodality imaging. It consists of a Fe₃O₄ nanocluster core, a carbon sandwiched layer, and a carbocyanine‐Gd^III (Cy‐Gd^III) coordination polymer outer shell (Fe₃O₄@C@Cy‐Gd^III). Folic acid‐conjugated poly(ethylene glycol) chains are embedded within the coordination polymer shell to achieve extended circulation and targeted delivery of probe particles in vivo. Control of Fe₃O₄ core grain sizes results in optimal r₂ relaxivity (224.5 × 10^–3 m ⁻¹ s^‐1) for T₂‐weighted magnetic resonance imaging. Cy‐Gd^III coordination polymers are also regulated to obtain a maximum 25.1% of Cy ligands and 5.2% of Gd^III ions for near‐infrared fluorescence and T₁‐weighted magnetic resonance imaging, respectively. The results demonstrate their impressive abilities for targeted, multimodal, and reliable imaging.