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1.
Adv Mater ; : e2309015, 2024 May 07.
Artigo em Italiano | MEDLINE | ID: mdl-38714305

RESUMO

Topological bosonic systems have recently aroused intense interests in exploring exotic phenomena that have no counterparts in electronic systems. The squeezed bosonic interaction in these systems is particularly interesting, because it can modify the vacuum fluctuations of topological states, drive them into instabilities, and lead to topological parametric oscillators. However, these phenomena remain experimentally elusive because of limited nonlinearities in most existing topological bosonic systems. Here, a topological parametric phonon oscillator is experimentally realized based on a nonlinear nanoelectromechanical Dirac-vortex cavity with strong squeezed interaction. Specifically, the Dirac-vortex cavity is parametrically driven to provide phase-sensitive amplification for topological phonons, leading to the observation of coherent parametric phonon oscillation above the threshold. Additionally, it is confirmed that the random frequency variation caused by fabrication disorders can be suppressed effectively by increasing the cavity size, while the free spectral range reduces at a much slower rate, which benefit the realization of large-area single-mode lasers. Our results represent an important advance in experimental investigations of topological physics with large bosonic nonlinearities and parametric gain. This article is protected by copyright. All rights reserved.

2.
RSC Adv ; 14(18): 12911-12922, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38650688

RESUMO

Thermal insulation materials with good flame-retardant properties have attracted widespread attention because of their huge application potential. Traditional petrochemical-based polymer insulation materials are flammable and have problems with environmental pollution. The microtubule structure is a perfect microstructure with excellent thermal insulation performance. In addition, the microtubule structure also has low density and high elasticity. Therefore, the microtubule structure is an important reference microstructure for the development of efficient thermal insulation materials. In this paper, a cellulose/SiO2 composite microtube thermal insulation superfoam has been successfully prepared. Cellulose microtubules were successfully prepared from poplar sawdust by chemical methods. The SiO2 aerogel precursor solution can be quickly adsorbed by the delignified cellulose microtubes. The SiO2 aerogel shells are evenly distributed only on the inner and outer walls of the delignified cellulose microtubes. The cellulose/SiO2 microtube composite (CSMC) superfoam exhibits low density, good mechanical properties, and low thermal conductivity (as low as 0.042 ± 0.0018 W m-1 K-1). The CSMC superfoam exhibits excellent self-extinguishing and flame-retardant properties. After being burned by a butane flame, the superfoam still has certain mechanical properties. The thermal conductivity of the B-CSMC superfoam (the CSMC superfoam burned by a butane flame) is about 0.050 W m-1 K-1. The B-CSMC superfoam remained almost unchanged after being continuously ablated by a butane flame for 3600 seconds.

3.
Light Sci Appl ; 13(1): 99, 2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38679604

RESUMO

Bloch oscillations (BOs), an important transport phenomenon, have been studied extensively in static systems but remain mysterious in Floquet systems. Here, by harnessing notions from photonic analogy, we propose a generalization of the existing BOs in photonic Floquet lattices, namely the "photonic Floquet-Bloch oscillations", which refer to rescaled photonic Bloch oscillations with a period of extended least common multiple of the modulation period and the Bloch oscillation period. Next, we report the first visual observation of such photonic Floquet-Bloch oscillations (FBOs) by employing waveguide fluorescence microscopy. Most significantly, the FBOs surpass the existing BOs in Floquet systems and exhibit exotic properties on their own, including fractal spectrum and fractional Floquet tunneling. This new transport mechanism offers an intriguing method of wave manipulation that may contribute to rapidly developing fields in photonics, condensed matter physics, and quantum physics.

4.
Opt Express ; 32(6): 10703-10714, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38571275

RESUMO

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.

5.
RSC Adv ; 14(11): 7350-7358, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38433938

RESUMO

High-performance thermal insulation materials with broad application prospects have attracted great attention. The introduction of new microstructures into thermal protection materials can significantly improve the thermal insulation performance. The tubular microstructure has obvious advantages such as thermal insulation, lightweight, mechanical, and other properties. Therefore, the microtubular structure has become an important reference microstructure for the development of high-performance thermal insulation materials. In this paper, the carbon/ZrO2 aerogel composite microtube superfoams with excellent thermal protection properties were prepared by a vacuum filtration and high-temperature carbonization method. The ZrO2 aerogel precursor solution can be quickly and uniformly adsorbed on the inner and outer walls of cellulose microtubules. These adsorbed ZrO2 aerogel precursor solution films can be converted into ZrO2 alcohol gel shells under the acceleration and promotion effect of citric acid at 65 °C. The micromorphology of the ZrO2 aerogel shell on the inner and outer walls of the composite microtubes can be efficiently controlled by the concentration of the ZrO2 aerogel precursor solution and the carbonization temperature. The carbon/ZrO2 aerogel composite microtube superfoam exhibits a lower thermal conductivity, lower density, good mechanical properties, and high ablation resistance. The thermal conductivity of the carbon/ZrO2 aerogel composite microtube superfoam is as low as 0.040 ± 0.001 W m-1 K-1. The residual rate of the carbon/ZrO2 aerogel composite microtube superfoam is still as high as 84.33% after butane flame ablation for up to 3600 seconds.

6.
Sci Adv ; 9(43): eadj3476, 2023 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-37889979

RESUMO

Metal halide perovskites have shown outstanding optoelectronic and nonlinear optical properties; yet, to realize wafer-scale high-performance perovskite-integrated photonics, the materials also need to have excellent ambient stability and compatibility with nanofabrication processes. In this work, we introduce Dion-Jacobson (D-J) phase perovskites for photonic device applications. By combining self-assembled monolayer-assisted film growth with thermal pressing, we obtain a series of compact and extremely smooth D-J phase perovskite thin films that exhibit excellent stability during electron-beam lithography, solvent development, and rinse. Combining spectroscopic and morphological characterizations, we further demonstrate how organic spacers can be used to fine-tune the photophysical properties and processability of the perovskite films. The distributed-feedback lasers based on the D-J phase perovskites exhibit a low lasing threshold (5.5 µJ cm-2 pumped with nanosecond laser), record high Q factor (up to 30,000), and excellent stability, with an unencapsulated device demonstrating a T90 beyond 60 hours in ambient conditions (50% relative humidity).

7.
Light Sci Appl ; 12(1): 255, 2023 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-37872140

RESUMO

Robust laser sources are a fundamental building block for contemporary information technologies. Originating from condensed-matter physics, the concept of topology has recently entered the realm of optics, offering fundamentally new design principles for lasers with enhanced robustness. In analogy to the well-known Majorana fermions in topological superconductors, Dirac-vortex states have recently been investigated in passive photonic systems and are now considered as a promising candidate for robust lasers. Here, we experimentally realize the topological Dirac-vortex microcavity lasers in InAs/InGaAs quantum-dot materials monolithically grown on a silicon substrate. We observe room-temperature continuous-wave linearly polarized vertical laser emission at a telecom wavelength. We confirm that the wavelength of the Dirac-vortex laser is topologically robust against variations in the cavity size, and its free spectral range defies the universal inverse scaling law with the cavity size. These lasers will play an important role in CMOS-compatible photonic and optoelectronic systems on a chip.

8.
J Am Chem Soc ; 145(35): 19265-19273, 2023 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-37625118

RESUMO

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.


Assuntos
Alcenos , Elétrons , Tomografia por Emissão de Pósitrons , Radioquímica , Compostos Radiofarmacêuticos
9.
Front Med (Lausanne) ; 10: 1199146, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37441689

RESUMO

Chimeric antigen receptor (CAR) T-cell therapies have evolved as breakthrough treatment options for the management of hematological malignancies and are also being developed as therapeutics for solid tumors. However, despite the impressive patient responses from CD19-directed CAR T-cell therapies, ~ 40%-60% of these patients' cancers eventually relapse, with variable prognosis. Such relapses may occur due to a combination of molecular resistance mechanisms, including antigen loss or mutations, T-cell exhaustion, and progression of the immunosuppressive tumor microenvironment. This class of therapeutics is also associated with certain unique toxicities, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and other "on-target, off-tumor" toxicities, as well as anaphylactic effects. Furthermore, manufacturing limitations and challenges associated with solid tumor infiltration have delayed extensive applications. The molecular imaging modalities of immunological positron emission tomography and single-photon emission computed tomography (immuno-PET/-SPECT) offer a target-specific and highly sensitive, quantitative, non-invasive platform for longitudinal detection of dynamic variations in target antigen expression in the body. Leveraging these imaging strategies as guidance tools for use with CAR T-cell therapies may enable the timely identification of resistance mechanisms and/or toxic events when they occur, permitting effective therapeutic interventions. In addition, the utilization of these approaches in tracking the CAR T-cell pharmacokinetics during product development and optimization may help to assess their efficacy and accordingly to predict treatment outcomes. In this review, we focus on current challenges and potential opportunities in the application of immuno-PET/-SPECT imaging strategies to address the challenges encountered with CAR T-cell therapies.

10.
Opt Lett ; 48(12): 3267-3270, 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-37319078

RESUMO

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.


Assuntos
Óxidos , Fótons
11.
Nano Lett ; 23(8): 3209-3216, 2023 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-37040479

RESUMO

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.

12.
Tomography ; 9(2): 567-578, 2023 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-36961005

RESUMO

We have integrated a compact and lightweight PET with an existing CT image-guided small animal irradiator to enable practical onboard PET/CT image-guided preclinical radiation therapy (RT) research. The PET with a stationary and full-ring detectors has ~1.1 mm uniform spatial resolution over its imaging field-of-view of 8.0 cm diameter and 3.5 cm axial length and was mechanically installed inside the irradiator in a tandem configuration with CT and radiation unit. A common animal bed was used for acquiring sequential dual functional and anatomical images with independent PET and CT control and acquisition systems. The reconstructed dual images were co-registered based on standard multi-modality image calibration and registration processes. Phantom studies were conducted to evaluate the integrated system and dual imaging performance. The measured mean PET/CT image registration error was ~0.3 mm. With one-bed and three-bed acquisitions, initial tumor focused and whole-body [18F]FDG animal images were acquired to test the capability of onboard PET/CT image guidance for preclinical RT research. Overall, the results have shown that integrated PET/CT/RT can provide advantageous and practical onboard PET/CT image to significantly enhance the accuracy of tumor delineation and radiation targeting that should enhance the existing and enable new and potentially breakthrough preclinical RT research and applications.


Assuntos
Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Radioterapia (Especialidade) , Animais , Fluordesoxiglucose F18 , Imagens de Fantasmas
13.
Pharmaceutics ; 15(2)2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36839802

RESUMO

After androgen deprivation therapy, a significant number of prostate cancer cases progress with a therapy-resistant neuroendocrine phenotype (NEPC). This represents a challenge for diagnosis and treatment. Based on our previously reported design of theranostic small-molecule prodrug conjugates (T-SMPDCs), herein we report a T-SMPDC tailored for targeted positron emission tomography (PET) imaging and chemotherapy of NEPC. The T-SMPDC is built upon a triazine core (TZ) to present three functionalities: (1) a chelating moiety (DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) for PET imaging when labeled with 68Ga (t1/2 = 68 min) or other relevant radiometals; (2) an octreotide (Octr) that targets the somatostatin receptor 2 (SSTR2), which is overexpressed in the innervated tumor microenvironment (TME); and (3) fingolimod, FTY720-an antagonist of sphingosine kinase 1 that is an intracellular enzyme upregulated in NEPC. Polyethylene glycol (PEG) chains were incorporated via conventional conjugation methods or a click chemistry reaction forming a 1,4-disubstituted 1,2,3-triazole (Trz) linkage for the optimization of in vivo kinetics as necessary. The T-SMPDC, DOTA-PEG3-TZ(PEG4-Octr)-PEG2-Trz-PEG3-Val-Cit-pABOC-FTY720 (PEGn: PEG with n repeating ethyleneoxy units (n = 2, 3, or 4); Val: valine; Cit: citrulline; pABOC: p-amino-benzyloxycarbonyl), showed selective SSTR2 binding and mediated internalization of the molecule in SSTR2 high cells. Release of FTY720 was observed when the T-SMPDC was exposed to cathepsin B, and the released FTY720 exerted cytotoxicity in cells. In vivo PET imaging showed significantly higher accumulation (2.1 ± 0.3 %ID/g; p = 0.02) of [68Ga]Ga-DOTA-PEG3-TZ(PEG4-Octr)-PEG2-Trz-PEG3-Val-Cit-pABOC-FTY720 in SSTR2high prostate cancer xenografts than in the SSTR2low xenografts (1.5 ± 0.4 %ID/g) at 13 min post-injection (p.i.) with a rapid excretion through the kidneys. Taken together, these proof-of-concept results validate the design concept of the T-SMPDC, which may hold a great potential for targeted diagnosis and therapy of NEPC.

14.
Rep Prog Phys ; 86(2)2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36167057

RESUMO

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.

15.
Sci Adv ; 8(50): eabp8293, 2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36525494

RESUMO

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Camundongos , Animais , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Glutaminase/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Glutamina/metabolismo , Isocitrato Desidrogenase
16.
Light Sci Appl ; 11(1): 328, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36400757

RESUMO

Bound states in the continuum (BICs) are a type of waves that are perfectly confined in the continuous spectrum of radiating waves without interaction with them. Here, we fabricated, with CMOS-compatible processes on a silicon chip, a wheel-shaped optomechanical microresonator, in which we experimentally observed the BIC in the micromechanical domain. The BIC results from destructive interference between two dissipative mechanical modes of the microresonator under broken azimuthal symmetry. Such BICs can be obtained from devices with large and robust supporting structures with variable sizes, which substantially reduces fabrication difficulty and allows for versatile application environments. Our results open a new way of phonon trapping in micromechanical structures with dissipation channels, and produce long phonon lifetimes that are desired in many mechanical applications such as mechanical oscillators, sensors, and quantum information processors.

17.
Opt Express ; 30(15): 26620-26627, 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-36236850

RESUMO

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.

18.
Clin Cancer Res ; 28(22): 4907-4916, 2022 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-36074149

RESUMO

PURPOSE: Immune checkpoint inhibitors (ICI) targeting the programmed cell death protein 1 and its ligand (PD-1/PD-L1) have transformed the treatment paradigm for metastatic renal cell carcinoma (RCC). However, response rates to ICIs as single agents or in combination vary widely and predictive biomarkers are lacking. Possibly related to the heterogeneity and dynamic nature of PD-L1 expression, tissue-based methods have shown limited value. Immuno-positron emission tomography (immunoPET) may enable noninvasive, comprehensive, and real-time PD-L1 detection. Herein, we systematically examined the performance of immunoPET for PD-L1 detection relative to IHC in an RCC patient-derived tumorgraft (TG) platform. EXPERIMENTAL DESIGN: Eight independent RCC TGs with a wide range of PD-L1 expression (0%-85%) were evaluated by immunoPET. Uptake of 89Zr-labeled atezolizumab ([89Zr]Zr-DFO-ATZ) was compared with PD-L1 expression in tumors by IHC through double-blind analyses. Clinical outcomes of ICI-treated patients whose TGs were examined were analyzed to evaluate the clinical role of immunoPET in RCC. RESULTS: ImmunoPET with [89Zr]Zr-DFO-ATZ (day 6/7 postinjection) revealed a statistically significant association with PD-L1 IHC assays (P = 0.0014; correlation ρXY = 0.78). Furthermore, immunoPET can be used to assess the heterogeneous distribution of PD-L1 expression. Finally, studies in the corresponding patients (n = 4) suggest that PD-L1 signal may influence ICI responsiveness. CONCLUSIONS: ImmunoPET with [89Zr]Zr-DFO-ATZ may enable a thorough and dynamic assessment of PD-L1 across sites of disease. The power of immunoPET to predict ICI response in RCC is being explored in an ongoing clinical trial (NCT04006522).


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Antígeno B7-H1/metabolismo , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/tratamento farmacológico , Radioisótopos , Distribuição Tecidual , Zircônio , Ensaios Clínicos como Assunto
19.
Int J Mol Sci ; 23(13)2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35806163

RESUMO

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.


Assuntos
Pró-Fármacos , Neoplasias da Próstata , Antígenos de Superfície/metabolismo , Linhagem Celular Tumoral , Preparações de Ação Retardada , Glutamato Carboxipeptidase II/metabolismo , Humanos , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Medicina de Precisão , Pró-Fármacos/farmacologia , Neoplasias da Próstata/metabolismo , Receptor 7 Toll-Like , Ureia
20.
ACS Infect Dis ; 8(8): 1663-1673, 2022 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-35869564

RESUMO

The increasing prevalence and severity of invasive fungal infections (IFIs), especially in immunocompromised populations, has amplified the need for rapid diagnosis of fungal pathogens. Radiotracers derived from d-amino acids (DAAs) show promise as bacterial-specific positron emission tomography (PET) imaging agents due to their preferential consumption by bacteria and largely nonutilization by hosts. Unlike mammals, fungi can utilize external DAAs including d-glutamine for their growth by rapidly upregulating DAA oxidases. Additionally, glutamine is essential for fungal nitrogen assimilation, survival, and virulence. We previously validated d-[5-11C]-glutamine (d-[5-11C]-Gln) as an efficient radiotracer targeting live bacterial soft-tissue infections. Here, we further expanded this investigation to evaluate its translational potential for PET imaging of IFIs in immunocompetent mouse models subcutaneously (SubQ) and intramuscularly (IM) infected with Candida albicans (C. albicans), using its l-isomer counterpart (l-[5-11C]-Gln) as a control. Comparative studies between pathogens showed significantly (p < 0.05) higher uptake in fungi (C. albicans and C. tropicalis) versus tested bacterial species for d-[5-11C]-Gln, suggesting that it could potentially serve as a more sensitive radiotracer for detection of fungal infections. Additionally, comparative PET imaging studies in immunocompetent infected mice demonstrated significantly higher infection-to-background ratios for d- versus l-[5-11C]-Gln in both SubQ (ratio = 1.97, p = 0.043) and IM (ratio = 1.97, p = 0.028) infections. Fungal infection imaging specificity was confirmed with no significant difference observed between localized inflammation sites versus untreated muscle background (heat-killed injection site/untreated muscle: ∼1.1). Taken together, this work demonstrates the translational potential of d-[5-11C]-Gln for noninvasive PET imaging of IFIs.


Assuntos
Infecções Fúngicas Invasivas , Micoses , Animais , Candida albicans , Glutamina/química , Mamíferos , Camundongos , Tomografia por Emissão de Pósitrons
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