Role of Redox‐Inactive Transition‐Metals in the Behavior of Cation‐Disordered Rocksalt Cathodes

Owing to the capacity boost from oxygen redox activities, Li‐rich cation‐disordered rocksalts (LRCDRS) represent a new class of promising high‐energy Li‐ion battery cathode materials. Redox‐inactive transition‐metal (TM) cations, typically d⁰ TM, are essential in the formation of rocksalt phases, however, their role in electrochemical performance and cathode stability is largely unknown. In the present study, the effect of two d⁰ TM (Nb⁵⁺ and Ti⁴⁺) is systematically compared on the redox chemistry of Mn‐based model LRCDRS cathodes, namely Li_1.3Nb_0.3Mn_0.4O₂ (LNMO), Li_1.25Nb_0.15Ti_0.2Mn_0.4O₂ (LNTMO), and Li_1.2Ti_0.4Mn_0.4O₂ (LTMO). Although electrochemically inactive, d⁰ TM serves as a modulator for oxygen redox, with Nb⁵⁺ significantly enhancing initial charge storage contribution from oxygen redox. Further studies using differential electrochemical mass spectroscopy and resonant inelastic X‐ray scattering reveal that Ti⁴⁺ is better in stabilizing the oxidized oxygen anions (O^n?, 0 < n < 2), leading to a more reversible O redox process with less oxygen gas release. As a result, much improved chemical, structural and cycling stabilities are achieved on LTMO. Detailed evaluation on the effect of d⁰ TM on degradation mechanism further suggests that proper design of redox‐inactive TM cations provides an important avenue to balanced capacity and stability in this newer class of cathode materials.     

Size‐Optimized Ultrasmall Porous Silica Nanoparticles Depict Vasculature‐Based Differential Targeting in Triple Negative Breast Cancer

Rapid sequestration and prolonged retention of intravenously injected nanoparticles by the liver and spleen (reticuloendothelial system (RES)) presents a major barrier to effective delivery to the target site and hampers clinical translation of nanomedicine. Inspired by biological macromolecular drugs, synthesis of ultrasmall (diameter ≈12–15 nm) porous silica nanoparticles (UPSNs), capable of prolonged plasma half‐life, attenuated RES sequestration, and accelerated hepatobiliary clearance, is reported. The study further investigates the effect of tumor vascularization on uptake and retention of UPSNs in two mouse models of triple negative breast cancer with distinctly different microenvironments. A semimechanistic mathematical model is developed to gain mechanistic insights into the interactions between the UPSNs and the biological entities of interest, specifically the RES. Despite similar systemic pharmacokinetic profiles, UPSNs demonstrate strikingly different tumor responses in the two models. Histopathology confirms the differences in vasculature and stromal status of the two models, and corresponding differences in the microscopic distribution of UPSNs within the tumors. The studies demonstrate the successful application of multidisciplinary and complementary approaches, based on laboratory experimentation and mathematical modeling, to concurrently design optimized nanomaterials, and investigate their complex biological interactions, in order to drive innovation and translation.     

SPECT reconstruction with sub‐sinogram acquisitions

Described herein are the advantages of using sub‐sinograms for single photon emission computed tomography image reconstruction. A sub‐sinogram is a sinogram acquired with an entire data acquisition protocol, but in a fraction of the total acquisition time. A total‐sinogram is the summation of all sub‐sinograms. Images can be reconstructed from the total‐sinogram or from sub‐sinograms and then be summed to produce the final image. For a linear reconstruction method such as the filtered backprojection algorithm, there is no advantage of using sub‐sinograms. However, for nonlinear methods such as the maximum likelihood (ML) expectation maximization algorithm, the use of sub‐sinograms can produce better results. The ML estimator is a random variable, and one ML reconstruction is one realization of the random variable. The ML solution is better obtained via the mean value of the random variable of the ML estimator. Sub‐sinograms can provide many realizations of the ML estimator. We show that the use of sub‐sinograms can produce better estimations for the ML solution than can the total‐sinogram and can also reduce the statistical noise within iteratively reconstructed images. © 2011 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 21, 247–252, 2011;     

Cyclo(RGD)‐Decorated Reduction‐Responsive Nanogels Mediate Targeted Chemotherapy of Integrin Overexpressing Human Glioblastoma In Vivo

Cyclo(Arg‐Gly‐Asp) peptide (cRGD) decorated disulfide (SS) containing poly(vinyl alcohol) nanogels (cRGD‐SS‐NGs) with an average diameter of 142 nm prepared by inverse nanoprecipitation, “click” reaction, and cRGD conjugation are developed for targeted treatment of integrin overexpressing human glioblastoma in vivo. Doxorubicin (DOX) release from cRGD‐SS‐NGs is highly inhibited under physiological conditions, while accelerated at endosomal pH and in response to cytoplasmic concentration of glutathione. Confocal microscopy shows that cRGD‐SS‐NGs facilitate the cellular uptake and intracellular DOX release in α_vβ₃ integrin overexpressing human glioblastoma U87‐MG cells. DOX‐loaded cRGD‐SS‐NGs present much better killing activity toward U87‐MG cells than that for nontargeted nanogels determined by MTT assay. The in vivo imaging and biodistribution studies reveal that DOX‐loaded cRGD‐SS‐NGs have a much better tumor targetability toward human U87‐MG glioblastoma xenograft in nude mice. Also the tumor growth is effectively inhibited by treatment with DOX‐loaded cRGD‐SS‐NGs, while continuous tumor growth is observed for mice treated with nondecorated nanogels as well as free DOX. Furthermore, the treatment with DOX‐loaded cRGD‐SS‐NGs has much fewer side effects, rendering these nanogels as a new platform for cancer chemotherapy in vivo.     

Writing,Self‐Healing,and Self‐Erasing on Conductive Pressure‐Sensitive Adhesives

A simple strategy for enabling conductive pressure sensitive adhesives (PSAs) to work as light‐responsive materials is reported. Direct laser‐writing of PSA substrates was achieved by means of a continuous‐wave He‐Ne laser focused through the objectives of an optical microscope. This approach takes advantage of cooperative interplay between viscoelastic properties of PSAs and enhanced thermal conductivity provided by an extra overlayer of gold. In particular, the thickness of the gold layer is a crucial parameter for tuning the substrate responsiveness. Self‐healing and self‐degradation processes can be exploited for controlling the lifetime of the written information, whereas additional protective coatings can be introduced to achieve permanent storage.     

Reassembly of 89Zr‐Labeled Cancer Cell Membranes into Multicompartment Membrane‐Derived Liposomes for PET‐Trackable Tumor‐Targeted Theranostics

Nanoengineering of cell membranes holds great potential to revolutionize tumor‐targeted theranostics, owing to their innate biocompatibility and ability to escape from the immune and reticuloendothelial systems. However, tailoring and integrating cell membranes with drug and imaging agents into one versatile nanoparticle are still challenging. Here, multicompartment membrane‐derived liposomes (MCLs) are developed by reassembling cancer cell membranes with Tween‐80, and are used to conjugate ⁸⁹Zr via deferoxamine chelator and load tetrakis(4‐carboxyphenyl) porphyrin for in vivo noninvasive quantitative tracing by positron emission tomography imaging and photodynamic therapy (PDT), respectively. Radiolabeled constructs, ⁸⁹Zr‐Df‐MCLs, demonstrate excellent radiochemical stability in vivo, target 4T1 tumors by the enhanced permeability and retention effect, and are retained long‐term for efficient and effective PDT while clearing gradually from the reticuloendothelial system via hepatobiliary excretion. Toxicity evaluation confirms that the MCLs do not impose acute or chronic toxicity in intravenously injected mice. Additionally, ⁸⁹Zr‐labeled MCLs can execute rapid and highly sensitive lymph node mapping, even for deep‐seated sentinel lymph nodes. The as‐developed cell membrane reassembling route to MCLs could be extended to other cell types, providing a versatile platform for disease theranostics by facilely and efficiently integrating various multifunctional agents.     

Toxic Reactive Oxygen Species Enhanced Synergistic Combination Therapy by Self‐Assembled Metal‐Phenolic Network Nanoparticles

Engineering functional nanomaterials with high therapeutic efficacy and minimum side effects has increasingly become a promising strategy for cancer treatment. Herein, a reactive oxygen species (ROS) enhanced combination chemotherapy platform is designed via a biocompatible metal‐polyphenol networks self‐assembly process by encapsulating doxorubicin (DOX) and platinum prodrugs in nanoparticles. Both DOX and platinum drugs can activate nicotinamide adenine dinucleotide phosphate oxidases, generating superoxide radicals (O₂^??). The superoxide dismutase‐like activity of polyphenols can catalyze H₂O₂ generation from O₂^??. Finally, the highly toxic HO^? free radicals are generated by a Fenton reaction. The ROS HO^? can synergize the chemotherapy by a cascade of bioreactions. Positron emission tomography imaging of ⁸⁹Zr‐labeled as‐prepared DOX@Pt prodrug Fe³⁺ nanoparticles (DPPF NPs) shows prolonged blood circulation and high tumor accumulation. Furthermore, the DPPF NPs can effectively inhibit tumor growth and reduce the side effects of anticancer drugs. This study establishes a novel ROS promoted synergistic nanomedicine platform for cancer therapy.     

Anionic Lipid,pH‐Sensitive Liposome‐Gold Nanoparticle Hybrids for Gene Delivery – Quantitative Research of the Mechanism

Gene therapy is a potential method for treating a large range of diseases. Gene vectors are widely used in gene therapy for promoting the gene delivery efficiency to the target cells. Here, gold nanoparticles (AuNPs) coated with dimethyldioctadecylammonium bromide (DODAB)/dioleoylphosphatidylethanolamine (DOPE) are synthesized using a facile method for a new gene vector (DODAB/DOPE‐AuNPs), which possess 3‐ and 1.5‐fold higher transfection efficiency than those of DODAB‐AuNPs and a commercial transfection agent, respectively. Meanwhile, it is nontoxic with concentrations required for effective gene delivery. Imaging and quantification studies of cellular uptake reveal that DOPE increases gene copies in cells, which may be attributed to the smaller size of AuNPs/DNA complexes. The dissociation efficiency of DNA from the endocytic pathway is quantified by incubating with different buffers and investigated directly in the cells. The results suggest that DOPE increases the internalization of AuNPs/DNA complexes and promotes DNA release from early endosomes for the vector is sensitive to the anionic lipid membrane and the decreasing pH along the endocytic pathway. The new vector contains the potential to be the new alternative as gene delivery vector for biomedical applications.     

System response matrix calculation using symmetries for dual‐head PET scanners

Positron emission tomography (PET) scanner with dual‐head geometry offers better spatial resolution and higher sensitivity for dedicated application when compared with conventional full‐ring PET scanners. However, this configuration suffers from limited‐angle projection and depth‐of‐interaction (DOI) effects. Accurate modeling of the system response matrix (SRM) and its incorporation into iterative methods can help to obtain images with better quality. In this paper, we proposed a line‐of‐response (LOR) based symmetry approach to calculate the SRM of PET scanners with dual‐head geometry. Both Monte Carlo (MC) and analytically computed SRMs were obtained and named MC SRM and geometrical SRM respectively, with their performances been compared using simulated phantom studies. The point source study shows that the resolution in directions parallel to the detector is rather uniform, with a full width at half maximum (FWHM) of 0.6～0.7 mm and 0.6～0.8 mm using MC and geometrical SRMs respectively. While the spatial resolution in the direction perpendicular to the detector is much worse, when moving towards the detector panel from the field‐of‐view (FOV) center, the FWHM changes from 1.5 mm to 1.8 mm and 2.4 mm to 3.1 mm using MC and geometrical SRMs, which is caused by the missing of projection views. Images generated using MC SRM also show better stochastic quality and quantitative performance. © 2013 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 23, 205–214, 2013     

Hierarchically Nanostructured Hybrid Platform for Tumor Delineation and Image‐Guided Surgery via NIR‐II Fluorescence and PET Bimodal Imaging

Bimodal imaging with fluorescence in the second near infrared window (NIR‐II) and positron emission tomography (PET) has important significance for tumor diagnosis and management because of complementary advantages. It remains challenging to develop NIR‐II/PET bimodal probes with high fluorescent brightness. Herein, bioinspired nanomaterials (melanin dot, mesoporous silica nanoparticle, and supported lipid bilayer), NIR‐II dye CH‐4T, and PET radionuclide ⁶⁴Cu are integrated into a hybrid NIR‐II/PET bimodal nanoprobe. The resultant nanoprobe exhibits attractive properties such as highly uniform tunable size, effective payload encapsulation, high stability, dispersibility, and biocompatibility. Interestingly, the incorporation of CH‐4T into the nanoparticle leads to 4.27‐fold fluorescence enhancement, resulting in brighter NIR‐II imaging for phantoms in vitro and in situ. Benefiting from the fluorescence enhancement, NIR‐II imaging with the nanoprobe is carried out to precisely delineate and resect tumors. Additionally, the nanoprobe is successfully applied in tumor PET imaging, showing the accumulation of the nanoprobe in a tumor with a clear contrast from 2 to 24 h postinjection. Overall, this hierarchically nanostructured platform is able to dramatically enhance fluorescent brightness of NIR‐II dye, detect tumors with NIR‐II/PET imaging, and guide intraoperative resection. The NIR‐II/PET bimodal nanoprobe has high potential for sensitive preoperative tumor diagnosis and precise intraoperative image‐guided surgery.     

Facile Fabrication of Tumor Redox‐Sensitive Nanoassemblies of Small‐Molecule Oleate Prodrug as Potent Chemotherapeutic Nanomedicine

The conjugate of paclitaxel (PTX) and docosahexaenoic acid has entered into clinical trials. However, the most recent clinical outcomes fell short of expectations, due to the extremely slow drug release from the hydrophobic conjugates. Herein, a novel prodrug‐based nanoplatform self‐assembled by the disulfide bond linked conjugates of PTX and oleic acid for rapid and differential release of PTX in tumor cells is reported. This redox‐responsive prodrug‐nanosystem demonstrates multiple therapeutic advantages, including one‐step facile fabrication, high drug‐loading efficiency (56%, w/w), on‐demand drug release responding to redox stimuli, as well as favorable cellular uptake and biodistribution. These advantages result in significantly enhanced antitumor efficacy in vivo, with the tumor almost completely disappearing in mice. Such a uniquely engineered prodrug‐nanosystem has great potential to be used as potent chemotherapeutic nanomedicine in clinical cancer therapy.     

Codelivery of Anti‐PD‐1 Antibody and Paclitaxel with Matrix Metalloproteinase and pH Dual‐Sensitive Micelles for Enhanced Tumor Chemoimmunotherapy

Immune checkpoint blockade (ICB) is demonstrating great potential in cancer immunotherapy nowadays. Yet, the low response rate to ICB remains an urgent challenge for tumor immunotherapy. A pH and matrix metalloproteinase dual‐sensitive micellar nanocarrier showing spatio‐temporally controlled release of anti‐PD‐1 antibody (aPD‐1) and paclitaxel (PTX) in solid tumors is prepared to realize synergistic cancer chemoimmunotherapy. Antitumor immunity can be activated by PTX‐induced immunogenic cell death (ICD), while aPD‐1 blocks the PD‐1/PD‐L1 axis to suppress the immune escape due to PTX‐induced PD‐L1 up‐regulation, thus resulting in a synergistic antitumor chemoimmunotherapy. Through decoration with a sheddable polyethylene glycol (PEG) shell, the nanodrug may better accumulate in tumors to boost the synergistic antitumor treatment in a mouse melanoma model. The present study demonstrates a potent antitumor chemoimmunotherapy utilizing tumor microenvironment‐sensitive micelles bearing a sheddable PEG layer to mediate site‐specific sequential release of aPD‐1 and PTX.     

Focused Ultrasound Enabled Trans‐Blood Brain Barrier Delivery of Gold Nanoclusters: Effect of Surface Charges and Quantification Using Positron Emission Tomography

Focused ultrasound (FUS) technology is reported to enhance the delivery of ⁶⁴Cu‐integrated ultrasmall gold nanoclusters (⁶⁴Cu‐AuNCs) across the blood‐brain barrier (BBB) as measured by positron emission tomography (PET). To better define the optimal physical properties for brain delivery, ⁶⁴Cu‐AuNCs with different surface charges are synthesized and characterized. In vivo biodistribution studies are performed to compare the individual organ uptake of each type of ⁶⁴Cu‐AuNCs. Quantitative PET imaging post‐FUS treatment shows site‐targeted brain penetration, retention, and diffusion of the negative, neutral, and positive ⁶⁴Cu‐AuNCs. Autoradiography is performed to compare the intrabrain distribution of these nanoclusters. PET Imaging demonstrates the effective BBB opening and successful delivery of ⁶⁴Cu‐AuNCs into the brain. Of the three ⁶⁴Cu‐AuNCs investigated, the neutrally charged nanostructure performs the best and is the candidate platform for future theranostic applications in neuro‐oncology.     

Redox‐Triggered Release of Moxifloxacin from Mesoporous Silica Nanoparticles Functionalized with Disulfide Snap‐Tops Enhances Efficacy Against Pneumonic Tularemia in Mice

Effective and rapid treatment of tularemia is needed to reduce morbidity and mortality of this potentially fatal infectious disease. The etiologic agent, Francisella tularensis, is a facultative intracellular bacterial pathogen which infects and multiplies to high numbers in macrophages. Nanotherapeutics are particularly promising for treatment of infectious diseases caused by intracellular pathogens, whose primary host cells are macrophages, because nanoparticles preferentially target and are avidly internalized by macrophages. A mesoporous silica nanoparticle (MSN) has been developed functionalized with disulfide snap‐tops that has high drug loading and selectively releases drug intracellularly in response to the redox potential. These nanoparticles, when loaded with Hoechst fluorescent dye, release their cargo exclusively intracellularly and stain the nuclei of macrophages. The MSNs loaded with moxifloxacin kill F. tularensis in macrophages in a dose‐dependent fashion. In a mouse model of lethal pneumonic tularemia, MSNs loaded with moxifloxacin prevent weight loss, illness, and death, markedly reduce the burden of F. tularensis in the lung, liver, and spleen, and are significantly more efficacious than an equivalent amount of free drug. An important proof‐of‐principle for the potential therapeutic use of a novel nanoparticle drug delivery platform for the treatment of infectious diseases is provided.     

Combined Positron Emission Tomography and Cerenkov Luminescence Imaging of Sentinel Lymph Nodes Using PEGylated Radionuclide‐Embedded Gold Nanoparticles

New imaging probes with high sensitivity and stability are urgently needed to accurately detect sentinel lymph nodes (SLNs) for successful cancer diagnosis. Herein, the use of highly sensitive and stable PEGylated radionuclide‐embedded gold nanoparticles (PEG‐RIe‐AuNPs) is reported for the detection of SLNs by combined positron emission tomography and Cerenkov luminescence imaging (PET/CLI). PEG‐RIe‐AuNPs show high sensitivity and stability both in vitro and in vivo, and are not toxic to normal ovarian and immune cells. In vivo PET/CLI imaging clearly reveals SLNs as early as 1 h post PEG‐RIe‐AuNP‐injection, with peak signals achieved at 6 h postinjection, which is consistent with the biodistribution results. Taken together, the data provide strong evidence that PEG‐RIe‐AuNPs are promising as potential lymphatic tracers in biomedical imaging for pre and intraoperative surgical guidance.