Polychromatic photonic Floquet-Bloch oscillations.

Photonic Floquet-Bloch oscillations (FBOs), a new type of Bloch-like oscillations in photonic Floquet lattices, have recently been observed as a typical discrete self-imaging effect. Here, we theoretically investigate the spectral range of approximate photonic Floquet-Bloch oscillations in arrays of evanescently coupled optical waveguides and show the adjustability of the spectral range. At an appropriate amplitude of the Floquet modulation, we have demonstrated approximate photonic FBOs over a broad spectral range, termed "polychromatic photonic Floquet-Bloch oscillations," which manifest as approximate self-imaging of polychromatic beams. Furthermore, by designing the functional form of the Floquet modulation, we can cascade two polychromatic photonic FBOs and further enhance the performance of polychromatic self-imaging. Our results provide a simple and novel mechanism for achieving polychromatic self-imaging in waveguide arrays and may find applications in polychromatic beam shaping and broadband optical signal processing.

Coupling of Photon Emitters in Monolayer WS2 with a Photonic Waveguide Based on Bound States in the Continuum.

On-chip light sources are an essential component of scalable photonic integrated circuits (PICs), and coupling between light sources and waveguides has attracted a great deal of attention. Photonic waveguides based on bound states in the continuum (BICs) allow optical confinement in a low-refractive-index waveguide on a high-refractive-index substrate and thus can be employed for constructing PICs. In this work, we experimentally demonstrated that the photoluminescence (PL) from a monolayer of tungsten sulfide (WS2) could be coupled into a BIC waveguide on a lithium-niobate-on-insulator (LNOI) substrate. Using finite-difference time-domain simulations, we numerically obtained a coupling efficiency of ∼2.3% for an in-plane-oriented dipole and a near-zero loss at a wavelength of 620 nm. By breaking through the limits of 2D-material integration with conventional photonic architectures, our work offers a new perspective for light-matter coupling in monolithic PICs.

One-Pot Formal Carboradiofluorination of Alkenes: A Toolkit for Positron Emission Tomography Imaging Probe Development.

We report the first one-pot formal alkene carboradiofluorination reaction employing easily accessible alkenes as both prosthetic group precursors and coupling partners. The methodology features rapid sequential Markovnikov-selective iodofluorination and photoinduced Pd(0/I/II)-catalyzed alkyl Heck reaction as a mild and robust fluorine-18 (18F) radiochemical approach for positron emission tomography (PET) imaging probe development. A new class of prosthetic groups for PET imaging probe synthesis was isolated as iodofluorinated intermediates in moderate to excellent yields. The one-pot formal alkenylfluorination reaction was carried out to produce over 30 analogues of a wide range of bioactive molecules. Further application of the Pd(0/I/II) manifold in PET probe development was illustrated by the direct carbo(radio)fluorination of electron-rich alkenes. The methods were successfully translated to radiolabel a broad scope of medicinally relevant small molecules in generally good radiochemical conversion. The protocol was further optimized to accommodate no-carrier-added conditions with similar efficiency for future (pre)clinical translation. Moreover, the radiosynthesis of prosthetic groups was automated in a radiochemistry module to facilitate its practical use in multistep radiochemical reactions.

2D-materials-integrated optoelectromechanics: recent progress and future perspectives.

The discovery of two-dimensional (2D) materials has gained worldwide attention owing to their extraordinary optical, electrical, and mechanical properties. Due to their atomic layer thicknesses, the emerging 2D materials have great advantages of enhanced interaction strength, broad operating bandwidth, and ultralow power consumption for optoelectromechanical coupling. The van der Waals (vdW) epitaxy or multidimensional integration of 2D material family provides a promising platform for on-chip advanced nano-optoelectromechanical systems (NOEMS). Here, we provide a comprehensive review on the nanomechanical properties of 2D materials and the recent advances of 2D-materials-integrated nano-electromechanical systems and nano-optomechanical systems. By utilizing active nanophotonics and optoelectronics as the interface, 2D active NOEMS and their coupling effects are particularly highlighted at the 2D atomic scale. Finally, we share our viewpoints on the future perspectives and key challenges of scalable 2D-materials-integrated active NOEMS for on-chip miniaturized, lightweight, and multifunctional integration applications.

High coupling efficiency waveguide grating couplers on lithium niobate.

We propose and validate a new, to the best of our knowledge, approach for high coupling efficiency (CE) grating couplers (GCs) in the lithium niobate on insulator photonic integration platform. Enhanced CE is achieved by increasing the grating strength using a high refractive index polysilicon layer on the GC. Due to the high refractive index of the polysilicon layer, the light in the lithium niobate waveguide is pulled up to the grating region. The optical cavity formed in the vertical direction enhances the CE of the waveguide GC. With this novel structure, simulations predicted the CE to be -1.40 dB, while the experimentally measured CE was -2.20 dB with a 3-dB bandwidth of 81 nm from 1592 nm to 1673 nm. The high CE GC is achieved without using bottom metal reflectors or requiring the etching of the lithium niobate material.

Hofstadter butterfly and topological edge states in a quasiperiodic photonic crystal cavity array.

Quasiperiodic structures with additional synthetic degrees of freedom have recently been recognized as a promising way for investigating high-dimensional topological phases with lower physical dimensions. Here, we investigated the well-known Harper-Aubry-André model on an integrated photonic platform by proposing a new design of a quasiperiodic photonic crystal (PhC) cavity array. This array is composed of closely coupled H1 PhC cavities with their cavity lengths being periodically modulated in the real space. The frequency spectrum of the structure shows the main features of the Hofstadter butterfly, which is one of the most important phenomena in the Harper-Aubry-André model. By varying the modulation phase, this structure exhibits nontrivial topology, which supports strongly localized topological edge states. These results have shown that quasiperiodic PhC cavity arrays can serve as the testbed for studying topological phases and new topological phenomena on an integrated platform.

Harnessing Dynamical Encircling of an Exceptional Point in Anti-PT-Symmetric Integrated Photonic Systems.

Dynamically encircling an exceptional point in a non-Hermitian system can lead to chiral behaviors, but this process is difficult for on-chip PT-symmetric devices which require accurate control of gain and loss rates. Here, we experimentally demonstrated encircling an exceptional point with a fixed loss rate in a compact anti-PT-symmetric integrated photonic system, where chiral mode switching was achieved within a length that is an order of magnitude shorter than that of a PT-symmetric system. Based on the experimental demonstration, we proposed a topologically protected mode (de)multiplexer that is robust against fabrication errors with a wide operating wavelength range. With the advantages of simplified fabrication and characterization processes, the demonstrated system can be used for studying higher-order exceptional points and for exotic light manipulation.

Targeting renal cell carcinoma with a HIF-2 antagonist.

Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau tumour suppressor gene (VHL). Because no other gene is mutated as frequently in ccRCC and VHL mutations are truncal, VHL inactivation is regarded as the governing event. VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 has been implicated in angiogenesis and multiple other processes, but angiogenesis is the main target of drugs such as the tyrosine kinase inhibitor sunitinib. HIF-2 has been regarded as undruggable. Here we use a tumourgraft/patient-derived xenograft platform to evaluate PT2399, a selective HIF-2 antagonist that was identified using a structure-based design approach. PT2399 dissociated HIF-2 (an obligatory heterodimer of HIF-2α-HIF-1ß) in human ccRCC cells and suppressed tumorigenesis in 56% (10 out of 18) of such lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumours, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant to PT2399. Resistance occurred despite HIF-2 dissociation in tumours and evidence of Hif-2 inhibition in the mouse, as determined by suppression of circulating erythropoietin, a HIF-2 target and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumours. Gene expression was largely unaffected by PT2399 in resistant tumours, illustrating the specificity of the drug. Sensitive tumours exhibited a distinguishing gene expression signature and generally higher levels of HIF-2α. Prolonged PT2399 treatment led to resistance. We identified binding site and second site suppressor mutations in HIF-2α and HIF-1ß, respectively. Both mutations preserved HIF-2 dimers despite treatment with PT2399. Finally, an extensively pretreated patient whose tumour had given rise to a sensitive tumourgraft showed disease control for more than 11 months when treated with a close analogue of PT2399, PT2385. We validate HIF-2 as a target in ccRCC, show that some ccRCCs are HIF-2 independent, and set the stage for biomarker-driven clinical trials.

Theranostic Small-Molecule Prodrug Conjugates for Targeted Delivery and Controlled Release of Toll-like Receptor 7 Agonists.

We previously reported the design and synthesis of a small-molecule drug conjugate (SMDC) platform that demonstrated several advantages over antibody-drug conjugates (ADCs) in terms of in vivo pharmacokinetics, solid tumor penetration, definitive chemical structure, and adaptability for modular synthesis. Constructed on a tri-modal SMDC platform derived from 1,3,5-triazine (TZ) that consists of a targeting moiety (Lys-Urea-Glu) for prostate-specific membrane antigen (PSMA), here we report a novel class of chemically identical theranostic small-molecule prodrug conjugates (T-SMPDCs), [18/19F]F-TZ(PSMA)-LEGU-TLR7, for PSMA-targeted delivery and controlled release of toll-like receptor 7 (TLR7) agonists to elicit de novo immune response for cancer immunotherapy. In vitro competitive binding assay of [19F]F-TZ(PSMA)-LEGU-TLR7 showed that the chemical modification of Lys-Urea-Glu did not compromise its binding affinity to PSMA. Receptor-mediated cell internalization upon the PSMA binding of [18F]F-TZ(PSMA)-LEGU-TLR7 showed a time-dependent increase, indicative of targeted intracellular delivery of the theranostic prodrug conjugate. The designed controlled release of gardiquimod, a TLR7 agonist, was realized by a legumain cleavable linker. We further performed an in vivo PET/CT imaging study that showed significantly higher uptake of [18F]F-TZ(PSMA)-LEGU-TLR7 in PSMA+ PC3-PIP tumors (1.9 ± 0.4% ID/g) than in PSMA- PC3-Flu tumors (0.8 ± 0.3% ID/g) at 1 h post-injection. In addition, the conjugate showed a one-compartment kinetic profile and in vivo stability. Taken together, our proof-of-concept biological evaluation demonstrated the potential of our T-SMPDCs for cancer immunomodulatory therapies.

PSMA-Targeting Imaging and Theranostic Agents-Current Status and Future Perspective.

In the past two decades, extensive efforts have been made to develop agents targeting prostate-specific membrane antigen (PSMA) for prostate cancer imaging and therapy. To date, represented by two recent approvals of [68Ga]Ga-PSMA-11 and [18F]F-DCFPyL by the United States Food and Drug Administration (US-FDA) for positron emission tomography (PET) imaging to identify suspected metastases or recurrence in patients with prostate cancer, PSMA-targeting imaging and theranostic agents derived from small molecule PSMA inhibitors have advanced to clinical practice and trials of prostate cancer. The focus of current development of new PSMA-targeting agents has thus shifted to the improvement of in vivo pharmacokinetics and higher specific binding affinity with the aims to further increase the detection sensitivity and specificity and minimize the toxicity to non-target tissues, particularly the kidneys. The main strategies involve systematic chemical modifications of the linkage between the targeting moiety and imaging/therapy payloads. In addition to a summary of the development history of PSMA-targeting agents, this review provides an overview of current advances and future promise of PSMA-targeted imaging and theranostics with focuses on the structural determinants of the chemical modification towards the next generation of PSMA-targeting agents.

Comparison of BMIPP-SPECT/CT to 18FDG-PET/CT for Imaging Brown or Browning Fat in a Preclinical Model.

Obesity is a leading cause of preventable death and morbidity. To elucidate the mechanisms connecting metabolically active brown adipose tissue (BAT) and metabolic health may provide insights into methods of treatment for obesity-related conditions. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT) is traditionally used to image human BAT activity. However, the primary energy source of BAT is derived from intracellular fatty acids and not glucose. Beta-methyl-p-iodophenylpentadecanoic acid (BMIPP) is a fatty acid analogue amenable to in vivo imaging by single photon emission computed tomography/CT (SPECT/CT) when radiolabeled with iodine isotopes. In this study, we compare the use of 18FDG-PET/CT and 125I-BMIPP-SPECT/CT for fat imaging to ascertain whether BMIPP is a more robust candidate for the non-invasive evaluation of metabolically active adipose depots. Interscapular BAT, inguinal white adipose tissue (iWAT), and gonadal white adipose tissue (gWAT) uptake of 18FDG and 125I-BMIPP was quantified in mice following treatment with the BAT-stimulating drug CL-316,243 or saline vehicle control. After CL-316,243 treatment, uptake of both radiotracers increased in BAT and iWAT. The standard uptake value (SUVmean) for 18FDG and 125I-BMIPP significantly correlated in these depots, although uptake of 125I-BMIPP in BAT and iWAT more closely mimicked the fold-change in metabolic rate as measured by an extracellular flux analyzer. Herein, we find that imaging BAT with the radioiodinated fatty acid analogue BMIPP yields more physiologically relevant data than 18FDG-PET/CT, and its conventional use may be a pivotal tool for evaluating BAT in both mice and humans.

Validation of SV2A-Targeted PET Imaging for Noninvasive Assessment of Neuroendocrine Differentiation in Prostate Cancer.

Neuroendocrine prostate cancer (NEPC) is an aggressive and lethal variant of prostate cancer (PCa), and it remains a diagnostic challenge. Herein we report our findings of using synaptic vesicle glycoprotein 2 isoform A (SV2A) as a promising marker for positron emission tomography (PET) imaging of neuroendocrine differentiation (NED). The bioinformatic analyses revealed an amplified SV2A gene expression in clinical samples of NEPC versus castration-resistant PCa with adenocarcinoma characteristics (CRPC-Adeno). Importantly, significantly upregulated SV2A protein levels were found in both NEPC cell lines and tumor tissues. PET imaging studies were carried out in NEPC xenograft models with 18F-SynVesT-1. Although 18F-SynVesT-1 is not a cancer imaging agent, it showed a significant uptake level in the SV2A+ tumor (NCI-H660: 0.70 ± 0.14 %ID/g at 50-60 min p.i.). The SV2A blockade resulted in a significant reduction of tumor uptake (0.25 ± 0.03 %ID/g, p = 0.025), indicating the desired SV2A imaging specificity. Moreover, the comparative PET imaging study showed that the DU145 tumors could be clearly visualized by 18F-SynVesT-1 but not 68Ga-PSMA-11 nor 68Ga-DOTATATE, further validating the role of SV2A-targeted imaging for noninvasive assessment of NED in PCa. In conclusion, we demonstrated that SV2A, highly expressed in NEPC, can serve as a promising target for noninvasive imaging evaluation of NED.

Combined Tumor Environment Triggered Self-Assembling Peptide Nanofibers and Inducible Multivalent Ligand Display for Cancer Cell Targeting with Enhanced Sensitivity and Specificity.

Many new technologies, such as cancer microenvironment-induced nanoparticle targeting and multivalent ligand approach for cell surface receptors, are developed for active targeting in cancer therapy. While the principle of each technology is well illustrated, most systems suffer from low targeting specificity and sensitivity. To fill the gap, this work demonstrates a successful attempt to combine both technologies to simultaneously improve cancer cell targeting sensitivity and specificity. Specifically, the main component is a targeting ligand conjugated self-assembling monomer precursor (SAM-P), which, at the tumor site, undergoes tumor-triggered cleavage to release the active form of self-assembling monomer capable of forming supramolecular nanostructures. Biophysical characterization confirms the chemical and physical transformation of SAM-P from unimers or oligomers with low ligand valency to supramolecular assemblies with high ligand valency under a tumor-mimicking reductive microenvironment. The in vitro fluorescence assay shows the importance of supramolecular morphology in mediating ligand-receptor interactions and targeting sensitivity. Enhanced targeting specificity and sensitivity can be achieved via tumor-triggered supramolecular assembly and induces multivalent ligand presentation toward cell surface receptors, respectively. The results support this combined tumor microenvironment-induced cell targeting and multivalent ligand display approach, and have great potential for use as cell-specific molecular imaging and therapeutic agents with high sensitivity and specificity.

Control of cerebral ischemia with magnetic nanoparticles.

The precise manipulation of microcirculation in mice can facilitate mechanistic studies of brain injury and repair after ischemia, but this manipulation remains a technical challenge, particularly in conscious mice. We developed a technology that uses micromagnets to induce aggregation of magnetic nanoparticles to reversibly occlude blood flow in microvessels. This allowed induction of ischemia in a specific cortical region of conscious mice of any postnatal age, including perinatal and neonatal stages, with precise spatiotemporal control but without surgical intervention of the skull or artery. When combined with longitudinal live-imaging approaches, this technology facilitated the discovery of a feature of the ischemic cascade: selective loss of smooth muscle cells in juveniles but not adults shortly after onset of ischemia and during blood reperfusion.

Graphene-assisted electro-optomechanical integration on a silicon-on-insulator platform.

Micro- and nano-optomechanics has attracted broad interest for applications of mechanical sensing and coherent signal processing. For nonpiezoelectric materials such as silicon or silicon nitride, electrocapacitive effects with metals patterned on mechanical structures are usually adopted to actuate the mechanical motion of the micro- or nanomechanical devices. However, the metals have deleterious effects on the mechanical structures because they add an additional weight and also introduce considerable mechanical losses. To solve these problems, we have proposed and experimentally demonstrated a new scheme of electro-optomechanical integration on a silicon-on-insulator platform by using single-layer graphene as a highly conductive coating for electromechanical actuation. Mechanical modes of different groups were electrically actuated and optically detected in a micromechanical resonator, with the mechanical Q > 1000 measured in air. Compatible with CMOS technology, our scheme is suitable for large-scale electro-optomechanical integration and will have wide applications in high-speed sensing, communication, and signal processing.

Functional imaging of RAS pathway targeting in malignant peripheral nerve sheath tumor cells and xenografts.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive form of soft-tissue sarcoma (STS) in children. Despite intensive therapy, relatively few children with metastatic and unresectable disease survive beyond three years. RAS pathway activation is common in MPNST, suggesting MEK pathway inhibition as a targeted therapy, but the impact on clinical outcome has been small to date. PROCEDURE: We conducted preclinical pharmacokinetic (PK) and pharmacodynamic studies of two MEK inhibitors, trametinib and selumetinib, in two MPNST models and analyzed tumors for intratumor drug levels. We then investigated 3'-deoxy-3'-[18 F]fluorothymidine (18 F-FLT) PET imaging followed by 18 F-FDG PET/CT imaging of MPNST xenografts coupled to short-term or longer-term treatment with selumetinib focusing on PET-based imaging as a biomarker of MEK inhibition. RESULTS: Trametinib decreased pERK expression in MPNST xenografts but did not prolong survival or decrease Ki67 expression. In contrast, selumetinib prolonged survival of animals bearing MPNST xenografts, and this correlated with decreased pERK and Ki67 staining. PK studies revealed a significantly higher fraction of unbound selumetinib within a responsive MPNST xenograft model. Thymidine uptake, assessed by 18 F-FLT PET/CT, positively correlated with Ki67 expression in different xenograft models and in response to selumetinib. CONCLUSION: The ability of MEK inhibitors to control MPNST growth cannot simply be predicted by serum drug levels or drug-induced changes in pERK expression. Tumor cell proliferation assessed by 18 F-FLT PET imaging might be useful as an early response marker to targeted therapies, including MEK inhibition, where a primary effect is cell-cycle arrest.

Inverse-designed low-loss and wideband polarization-insensitive silicon waveguide crossing.

Waveguide crossings are an essential component for constructing complex and functional on-chip photonic networks. Polarization-insensitive waveguide crossings are desired because photonic networks usually involve light with different polarizations. Here, we propose a polarization-insensitive waveguide crossing on a 250-nm silicon-on-insulator platform by using an inverse design method. In simulation, the designed waveguide crossing can maintain insertion loss below 0.18 (0.25) dB in the wavelength range of 1440-1640 nm for the TE0 (TM0) mode and achieve minimal insertion loss as small as 0.08 (0.07) dB at the wavelength of 1550 nm. The cross talk maintains below -32 dB and -35 dB for the TE0 and TM0 modes, respectively. Experimentally, the fabricated waveguide crossing achieves measured insertion loss less than 0.20 (0.25) dB for the TE0 (TM0) mode with minimal insertion loss as small as 0.1 dB. The measured cross talk is below -28 dB and -31 dB for the TE0 and TM0 modes, respectively. Therefore, our proposed waveguide crossing can be widely applied in photonic integrated circuits to construct photonic systems with the capabilities of polarization control and mode (de)multiplexing.

Giant enhancement of stimulated Brillouin scattering with engineered phoxonic crystal waveguides.

Stimulated Brillouin scattering (SBS) is a third-order nonlinear process that involves the interaction of two light fields and an acoustic wave in a medium. It has been exploited for applications of optical communication, sensing, and signal processing. This effect, originally demonstrated in long optical fibers, has recently been realized in silicon waveguides on a chip-scale integrated platform. However, due to the weak per-unit-length SBS gain, the length of the silicon waveguides is usually several centimeters, which prevents device miniaturization for high-density integration. Here, we engineer a phoxonic crystal waveguide structure to achieve significantly enhanced SBS gain in the entire C band, by taking advantage of its simultaneous confinement of slow propagating optical and acoustic waves. The resulting SBS gain coefficient is greater than 3 × 104 W-1 m-1 in the wavelength range of 1520-1565 nm with the highest value beyond 106 W-1 m-1, which is at least an order of magnitude higher than the existing demonstrations. This giant enhancement of SBS gain enables ultracompact and high-performance SBS-based integrated optoelectronic devices such as Brillouin lasers, amplifiers, and signal processors.

Ultranarrow-band metagrating absorbers for sensing and modulation.

Nanostructured plasmonic metamaterials are an excellent platform for narrowband optical absorption, which has wide applications in sensing, filtering, modulation, and emission tailoring. However, achieving a subnanometer absorption bandwidth for optical sensing and dynamical control of light is still challenging. Here, we propose an asymmetric metagrating structure and make use of the propagating surface plasmonic mode that has a small dissipation rate, to achieve perfect optical absorption with a bandwidth of 0.28 nm near the wavelength of 1.55 µm. Our proposed structure can be used in solution environments as a chemical or biological sensor in the visible spectral range just by changing the structural parameters. The sensor possesses a sensitivity of 440 nm/RIU and figure of merit of 1333.33 RIU-1. In addition, by combining an organic electro-optic material with this metagrating, our device can be reconfigurable with a dynamic range of 15.52 dB. Therefore, our proposed metagrating platform not only works as an ultranarrow-band absorber, but also can be employed for optical sensing and dynamic control of light.

Parity-time-symmetric mechanical systems by the cavity optomechanical effect.

Parity-time (PT) symmetry, an interesting concept originally introduced in quantum mechanics, has been extended to many other branches of physics. Besides its demonstrations in optics and electronics, the study of PT-symmetric mechanics is growing rapidly. To date, most PT-symmetric mechanical systems have relatively large size and low operating frequency, which limits their applications in high-speed sensing and signal processing. Here, we propose a PT-symmetric mechanical system with gain/loss provided by the cavity optomechanical effect, which can overcome those limitations. We theoretically analyze and numerically simulate the optical control of PT-symmetric optomechanical systems that consist of two or more mechanical resonators. We find the property of unidirectional reflection in these systems, which may pave the way for the study of topological acoustics and phononic signal processing.