Preoperative Detection and Intraoperative Visualization of Brain Tumors for More Precise Surgery: A New Dual‐Modality MRI and NIR Nanoprobe

In clinical practice, it is difficult to identify tumor margins during brain surgery due to its inherent infiltrative character. Herein, a unique dual‐modality nanoprobe (Gd‐DOTA‐Ag₂S QDs, referred as Gd‐Ag₂S nanoprobe) is reported, which integrates advantages of the deep tissue penetration of enhanced magnetic resonance (MR) imaging of Gd and the high signal‐to‐noise ratio and high spatiotemporal resolution of fluorescence imaging in the second near‐infrared window (NIR‐II) of Ag₂S quantum dots (QDs). Due to the abundant tumor angiogenesis and the enhanced permeability and retention effect in the tumor, a brain tumor (U87MG) in a mouse model is clearly delineated in situ with the help of the Gd assisted T1 MR imaging and the intraoperative resection of the tumor is precisely accomplished under the guidance of NIR‐II fluorescence imaging of Ag₂S QDs after intravenous injection of Gd‐Ag₂S nanoprobe. Additionally, no histologic changes are observed in the main organs of the mouse after administration of Gd‐Ag₂S nanoprobe for 1 month, indicating the high biocompatibility of the nanoprobe. We expect that such a novel “Detection and Operation” strategy based on Gd‐Ag₂S nanoprobe is promising in future clinical applications.     

Dual‐Stimuli Responsive Nanotheranostics for Multimodal Imaging Guided Trimodal Synergistic Therapy

Multimodal imaging guided synergistic therapy promises more accurate diagnosis than any single imaging modality, and higher therapeutic efficiency than any single one or their simple “mechanical” combination. Herein, we report a dual‐stimuli responsive nanotheranostic based on a hierarchical nanoplatform, composed of mesoporous silica‐coated gold nanorods (GNR@SiO2), Indocyanine Green (ICG), and 5‐fluorouracil (5‐FU), for in vivo multimodal imaging guided synergistic therapy. The 5‐FU loaded ICG‐conjugated silica‐coated gold nanorods (GNR@SiO2‐5‐FU‐ICG) was able to response specifically to the two stimuli of pH change and near‐infrared (NIR) light irradiation. Both the NIR light irradiation and acidic environment accelerated the 5‐FU release. Meanwhile, the heat generation and singlet oxygen production can be induced by GNR@SiO2‐5‐FU‐ICG upon light irradiation. Most intriguingly, the nanoplatform also promises multimodal imaging such as two‐photon luminescence, fluorescence, photoacoustic, photothermal imaging, as well as trimodal synergistic therapy such as photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy. The cancer theranostic capability of GNR@SiO2‐5‐FU‐ICG was evaluated both in vitro and in vivo. The trimodal synergistic therapy with the guidance of multimodal imaging exhibited remarkably enhanced treatment efficacy. This concept of a hierarchical nanoplatform integrates multiple diagnostic/therapeutic modalities into one platform, which can potentially be applied as personalized nanomedicine with drug delivery, diagnosis, and treatment.     

Responsive Upconversion Nanoprobe for Background‐Free Hypochlorous Acid Detection and Bioimaging

Responsive nanoprobes play an important role in bioassay and bioimaging, early diagnosis of diseases and treatment monitoring. Herein, a upconversional nanoparticle (UCNP)‐based nanoprobe, Ru@UCNPs, for specific sensing and imaging of hypochlorous acid (HOCl) is reported. This Ru@UCNP nanoprobe consists of two functional components,, i.e., NaYF₄:Yb, Tm UCNPs that can convert near infrared light‐to‐visible light as the energy donor, and a HOCl‐responsive ruthenium(II) complex [Ru(bpy)₂(DNCH‐bpy)](PF₆)₂ (Ru‐DNPH) as the energy acceptor and also the upconversion luminescence (UCL) quencher. Within this luminescence resonance energy transfer nanoprobe system, the UCL OFF–ON emission is triggered specifically by HOCl. This triggering reaction enables the detection of HOCl in aqueous solution and biological systems. As an example of applications, the Ru@UCNPs nanoprobe is loaded onto test papers for semiquantitative HOCl detection without any interference from the background fluorescence. The application of Ru@UCNPs for background‐free detection and visualization of HOCl in cells and mice is successfully demonstrated. This research has thus shown that Ru@UCNPs is a selective HOCl‐responsive nanoprobe, providing a new way to detect HOCl and a new strategy to develop novel nanoprobes for in situ detection of various biomarkers in cells and early disgnosis of animal diseases.     

Dual‐Modal NIR‐Fluorophore Conjugated Magnetic Nanoparticle for Imaging Amyloid‐β Species In Vivo

Senile plaques, the extracellular deposit of amyloid‐β (Aβ) peptides, are one of the neuropathological hallmarks found in Alzheimer's disease (AD) brain. The current method of brain imaging of amyloid plaques based on positron emission tomography (PET) is expensive and invasive with low spatial resolution. Thus, the development of sensitive and nonradiative amyloid‐β (Aβ)‐specific contrast agents is highly important and beneficial to achieve early AD detection, monitor the disease progression, and evaluate the effectiveness of potential AD drugs. Here a neuroprotective dual‐modal nanoprobe developed by integrating highly Aβ‐specific and turn‐on fluorescence cyanine sensors with superparamagnetic iron oxide nanoparticles as an effective near‐infrared imaging (NIRI)/magnetic resonance imaging (MRI) contrast agent for imaging of Aβ species in vivo is reported. This Aβ‐specific probe is found not only nontoxic and noninvasive, but also highly blood brain barrier permeable. It also shows a potent neuroprotective effect against Aβ‐induced toxicities. This nanoprobe is successfully applied for in vivo fluorescence imaging with high sensitivity and selectivity to Aβ species, and MRI with high spatial resolution in an APP/PS1 transgenic mice model. Its potential as a powerful in vivo dual‐modal imaging tool for early detection and diagnosis of AD in humans is affirmed.     

Miniature Hollow Gold Nanorods with Enhanced Effect for In Vivo Photoacoustic Imaging in the NIR‐II Window

The miniaturization of gold nanorods exhibits a bright prospect for intravital photoacoustic imaging (PAI) and the hollow structure possesses a better plasmonic property. Herein, miniature hollow gold nanorods (M‐AuHNRs) (≈46 nm in length) possessing strong plasmonic absorbance in the second near‐infrared (NIR‐II) window (1000–1350 nm) are developed, which are considered as the most suitable range for the intravital PAI. The as‐prepared M‐AuHNRs exhibit 3.5 times stronger photoacoustic signal intensity than the large hollow Au nanorods (≈105 nm in length) at 0.2 optical density under 1064 nm laser irradiation. The in vivo biodistribution measurement shows that the accumulation in tumor of miniature nanorods is twofold as high as that of the large counterpart. After modifying with a tumor‐targeting molecule and fluorochrome, in living tumor‐bearing mice, the M‐AuHNRs group gives a high fluorescence intensity in tumors, which is 3.6‐fold that of the large ones with the same functionalization. Moreover, in the intravital PAI of living tumor‐bearing mice, the M‐AuHNRs generate longer‐lasting and stronger photoacoustic signal than the large counterpart in the NIR‐II window. Overall, this study presents the fabrication of M‐AuHNRs as a promising contrast agent for intravital PAI.     

Manganese Doped Fluorescent Paramagnetic Nanocrystals for Dual‐Modal Imaging

In this work, dual‐modal (fluorescence and magnetic resonance) imaging capabilities of water‐soluble, low‐toxicity, monodisperse Mn‐doped ZnSe nanocrystals (NCs) with a size (6.5 nm) below the optimum kidney cutoff limit (10 nm) are reported. Synthesizing Mn‐doped ZnSe NCs with varying Mn²⁺ concentrations, a systematic investigation of the optical properties of these NCs by using photoluminescence (PL) and time resolved fluorescence are demonstrated. The elemental properties of these NCs using X‐ray photoelectron spectroscopy and inductive coupled plasma‐mass spectroscopy confirming Mn²⁺ doping is confined to the core of these NCs are also presented. It is observed that with increasing Mn²⁺ concentration the PL intensity first increases, reaching a maximum at Mn²⁺ concentration of 3.2 at% (achieving a PL quantum yield (QY) of 37%), after which it starts to decrease. Here, this high‐efficiency sample is demonstrated for applications in dual‐modal imaging. These NCs are further made water‐soluble by ligand exchange using 3‐mercaptopropionic acid, preserving their PL QY as high as 18%. At the same time, these NCs exhibit high relaxivity (≈2.95 mM^?1 s^?1) to obtain MR contrast at 25 °C, 3 T. Therefore, the Mn²⁺ doping in these water‐soluble Cd‐free NCs are sufficient to produce contrast for both fluorescence and magnetic resonance imaging techniques.     

Dual‐Functional Alginic Acid Hybrid Nanospheres for Cell Imaging and Drug Delivery

An effective and facile approach to prepare gold‐nanoparticle‐encapsulated alginic acid‐poly[2‐(diethylamino)ethyl methacrylate] monodisperse hybrid nanospheres (ALG–PDEA–Au) is developed by using monodisperse ALG–PDEA nanospheres as a precursor nanoparticulate reaction system. This approach utilizes particle‐interior chemistry, which avoids additional reductant or laborious separation process and, moreover, elegantly ensures that all the gold nanoparticles are located inside the hybrid nanospheres and every nanosphere is loaded with gold nanoparticles. These obtained ALG–PDEA–Au hybrid nanospheres have not only uniform size, similar surface properties, and good biocompatibility but also unique optical properties provided by the embedded gold nanoparticles. It is demonstrated that negatively charged ALG–PDEA–Au hybrid nanospheres can be internalized by human colorectal LoVo cancer cells and hence act as novel optical‐contrast reagents in tumor‐cell imaging by optical microscopy. Moreover, these hybrid nanospheres can also serve as biocompatible carriers for the loading and delivery of an anti‐cancer drug doxorubicin. In vitro cell viability tests reveal that drug‐loaded ALG–PDEA–Au hybrid nanospheres exhibit similar tumor cell inhibition to the free drug doxorubicin. Therefore, the obtained hybrid nanospheres successfully combine two functions, that is, cell imaging and drug delivery, into one single system, and may be of great application potential in other biomedical‐related areas.     

A Flexible Caterpillar‐Like Gold Nanoparticle Assemblies with Ultrasmall Nanogaps for Enhanced Dual‐Modal Imaging and Photothermal Therapy

Gold nanoparticle (AuNP) assemblies (GNAs) have attracted attention since enhanced coupling plasmonic resonance (CPR) emerged in the nanogap between coupling AuNPs. For one dimensional GNAs (1D‐GNAs), most CPR from the nanogaps could be easily activated by electromagnetic waves and generate drastically enhanced CPR because the nanogaps between coupling AuNPs are linearly distributed in the 1D‐GNAs. The reported studies focus on the synthesis of 1D‐GNAs and fundamental exploration of CPR. There are still problems which impede further applications in nanomedicine, such as big size (>500 nm), poor water solubility, and/or poor stability. In this study, a kind of 1D flexible caterpillar‐like GNAs (CL‐GNAs) with ultrasmall nanogaps, good water solubility, and good stability is developed. The CL‐GNAs have a flexible structure that can randomly move to change their morphology, which is rarely reported. Numerous ultrasmall nanogaps (<1 nm) are linearly distributed along the structure of CL‐GNAs and generate enhanced CPR. The toxicity assessments in vitro and vivo respectively demonstrate that CL‐GNAs have a low cytotoxicity and good biocompatibility. The CL‐GNAs can be used as an efficient photothermal agent for photothermal therapy, a probe for Raman imaging and photothermal imaging.     

Smart‐Dust‐Nanorice for Enhancement of Endogenous Raman Signal,Contrast in Photoacoustic Imaging,and T2‐Shortening in Magnetic Resonance Imaging

Raman microspectroscopy provides chemo‐selective image contrast, sub‐micrometer resolution, and multiplexing capabilities. However, it suffers from weak signals resulting in image‐acquisition times of up to several hours. Surface‐enhanced Raman scattering (SERS) can dramatically enhance signals of molecules in close vicinity of metallic surfaces and overcome this limitation. Multimodal, SERS‐active nanoparticles are usually labeled with Raman marker molecules, limiting SERS to the coating material. In order to realize multimodal imaging while acquiring the rich endogenous vibronic information of the specimen, a core–shell particle based on “Nanorice”, where a spindle‐shaped iron oxide core is encapsulated by a closed gold shell, is developed. An ultrathin layer of silica prevents agglomeration and unwanted chemical interaction with the specimen. This approach provides Raman signal enhancement due to plasmon resonance effects of the shell while the optical absorption in the near‐infrared spectral region provides contrast in photoacoustic tomography. Finally, T2‐relaxation of a magnetic resonance imaging (MRI) experiment is altered by taking advantage of the iron oxide core. The feasibility for Raman imaging is evaluated by nearfield simulations and experimental studies on the primate cell line COS1. MRI and photoacoustics are demonstrated in agarose phantoms illustrating the promising translational nature of this strategy for clinical applications in radiology.     

Bubble‐Sheet‐Like Interface Design with an Ultrastable Solid Electrolyte Layer for High‐Performance Dual‐Ion Batteries

In this work, a bubble‐sheet‐like hollow interface design on Al foil anode to improve the cycling stability and rate performance of aluminum anode based dual‐ion battery is reported, in which, a carbon‐coated hollow aluminum anode is used as both anode materials and current collector. This anode structure can guide the alloying position inside the hollow nanospheres, and also confine the alloy sizes within the hollow nanospheres, resulting in significantly restricted volumetric expansion and ultrastable solid electrolyte interface (SEI). As a result, the battery demonstrates an excellent long‐term cycling stability within 1500 cycles with ≈99% capacity retention at 2 C. Moreover, this cell displays an energy density of 169 Wh kg^?1 even at high power density of 2113 W kg^?1 (10 C, charge and discharge within 6 min), which is much higher than most of conventional lithium ion batteries. The interfacial engineering strategy shown in this work to stabilize SEI layer and control the alloy forming position could be generalized to promote the research development of metal anodes based battery systems.