7 research outputs found
Bottom-Up Synthesis of Metal-Ion-Doped WS<sub>2</sub> Nanoflakes for Cancer Theranostics
Recently, two-dimensional transition metal dichalcogenides (TMDCs) have received tremendous attention in many fields including biomedicine. Herein, we develop a general method to dope different types of metal ions into WS<sub>2</sub> nanoflakes, a typical class of TMDCs, and choose Gd<sup>3+</sup>-doped WS<sub>2</sub> (WS<sub>2</sub>:Gd<sup>3+</sup>) with polyethylene glycol (PEG) modification as a multifunctional agent for imaging-guided combination cancer treatment. While WS<sub>2</sub> with strong near-infrared (NIR) absorbance and X-ray attenuation ability enables contrasts in photoacoustic (PA) imaging and computed tomography (CT), Gd<sup>3+</sup> doping offers the nanostructure a paramagnetic property for magnetic resonance (MR) imaging. As revealed by trimodal PA/CT/MR imaging, WS<sub>2</sub>:Gd<sup>3+</sup>-PEG nanoflakes showed efficient tumor homing after intravenous injection. <i>In vivo</i> cancer treatment study further uncovered that WS<sub>2</sub>:Gd<sup>3+</sup>-PEG could not only convert NIR light into heat for photothermal therapy (PTT) but also enhance the ionizing irradiation-induced tumor damage to boost radiation therapy (RT). Owing to the improved tumor oxygenation after the mild PTT, the combination of PTT and RT induced by WS<sub>2</sub>:Gd<sup>3+</sup>-PEG resulted in a remarkable synergistic effect to destroy cancer. Our work highlights the promise of utilizing inherent physical properties of TMDC-based nanostructures, whose functions could be further enriched by elementary doping, for applications in multimodal bioimaging and synergistic cancer therapy
Antigen-Loaded Upconversion Nanoparticles for Dendritic Cell Stimulation, Tracking, and Vaccination in Dendritic Cell-Based Immunotherapy
A dendritic cell (DC) vaccine, which is based on efficient antigen delivery into DCs and migration of antigen-pulsed DCs to draining lymph nodes after vaccination, is an effective strategy in initiating CD8<sup>+</sup> T cell immunity for immunotherapy. Herein, antigen-loaded upconversion nanoparticles (UCNPs) are used to label and stimulate DCs, which could be precisely tracked after being injected into animals and induce an antigen-specific immune response. It is discovered that a model antigen, ovalbumin (OVA), could be adsorbed on the surface of dual-polymer-coated UCNPs <i>via</i> electrostatic interaction, forming nanoparticleāantigen complexes, which are efficiently engulfed by DCs and induce DC maturation and cytokine release. Highly sensitive <i>in vivo</i> upconversion luminescence (UCL) imaging of nanoparticle-labeled DCs is successfully carried out, observing the homing of DCs to draining lymph nodes after injection. In addition, strong antigen-specific immune responses including enhanced T cell proliferation, interferon gamma (IFN-Ī³) production, and cytotoxic T lymphocyte (CTL)-mediated responses are induced by a nanoparticle-pulsed DC vaccine, which is promising for DC-based immunotherapy potentially against cancer
Graphene-Based Nanocomposite As an Effective, Multifunctional, and Recyclable Antibacterial Agent
The
development of new antibacterial agents that are highly effective
are of great interest. Herein, we present a recyclable and synergistic
nanocomposite by growing both iron oxide nanoparticles (IONPs) and
silver nanoparticles (AgNPs) on the surface of graphene oxide (GO),
obtaining GO-IONP-Ag nanocomposite as a novel multifunctional antibacterial
material. Compared with AgNPs, which have been widely used as antibacterial
agents, our GO-IONP-Ag shows much higher antibacterial efficiency
toward both Gram-negative bacteria <i>Escherichia coli</i> (<i>E. coli</i>) and Gram-positive bacteria <i>Staphylococcus
aureus</i> (<i>S. aureus</i>). Taking the advantage
of its strong near-infrared (NIR) absorbance, photothermal treatment
is also conducted with GO-IONP-Ag, achieving a remarkable synergistic
antibacterial effect to inhibit <i>S. aureus</i> at a rather
low concentration of this agent. Moreover, with magnetic IONPs existing
in the composite, we can easily recycle GO-IONP-Ag by magnetic separation,
allowing its repeated use. Given the above advantages as well as its
easy preparation and cheap cost, GO-IONP-Ag developed in this work
may find potential applications as a useful antibacterial agent in
the areas of healthcare and environmental engineering
Hyaluronidase To Enhance Nanoparticle-Based Photodynamic Tumor Therapy
Photodynamic therapy (PDT) is considered
as a safe and selective way to treat a wide range of cancers as well
as nononcological disorders. However, as oxygen is required in the
process of PDT, the hypoxic tumor microenvironment has largely limited
the efficacy of PDT to treat tumors especially those with relatively
large sizes. To this end, we uncover that hyaluronidase (HAase), which
breaks down hyaluronan, a major component of extracellular matrix
(ECM) in tumors, would be able to enhance the efficacy of nanoparticle-based
PDT for in vivo cancer treatment. It is found that the administration
of HAase would lead to the increase of tumor vessel densities and
effective vascular areas, resulting in increased perfusion inside
the tumor. As a result, the tumor uptake of nanomicelles covalently
linked with chlorine e6 (NM-Ce6) would be increased by ā¼2 folds
due to the improved āenhanced permeability and retentionā
(EPR) effect, while the tumor oxygenation level also shows a remarkable
increase, effectively relieving the hypoxia state inside the tumor.
Those effects taken together offer significant benefits in greatly
improving the efficacy of PDT delivered by nanoparticles. Taking advantage
of the effective migration of HAase from the primary tumor to its
drainage sentinel lymph nodes (SLNs), we further demonstrate that
this strategy would be helpful to the treatment of metastatic lymph
nodes by nanoparticle-based PDT. Lastly, both enhanced EPR effect
of NM-Ce6 and relieved hypoxia state of tumor are also observed after
systemic injection of modified HAase, proving its potential for clinical
translation. Therefore, our work presents a new concept to improve
the efficacy of nanomedicine by modulating the tumor microenvironment
Dual-Modality Positron Emission Tomography/Optical Image-Guided Photodynamic Cancer Therapy with Chlorin e6-Containing Nanomicelles
Multifunctional
nanoparticles with combined diagnostic and therapeutic
functions show great promise in nanomedicine. Herein, we develop an
organic photodynamic therapy (PDT) system based on polyethylene glycol
(PEG)-coated nanomicelles conjugated with ā¼20% chlorin e6 (PEG-Ce
6 nanomicelles), which functions as an optical imaging agent, as well
as a PDT agent. The formed PEG-Ce 6 nanomicelles with the size of
ā¼20 nm were highly stable in various physiological solutions
for a long time. Moreover, Ce 6 can also be a <sup>64</sup>Cu chelating
agent for <i>in vivo</i> positron emission tomography (PET).
By simply mixing, more than 90% of <sup>64</sup>Cu was chelator-free
labeled on PEG-Ce 6 nanomicelles, and they also showed high stability
in serum conditions. Both fluorescence imaging and PET imaging revealed
that PEG-Ce 6 nanomicelles displayed high tumor uptake (13.7 Ā±
2.2%ID/g) after intravenous injection into tumor-bearing mice at the
48 h time point. In addition, PEG-Ce 6 nanomicelles exhibited excellent
PDT properties upon laser irradiation, confirming the theranostic
properties of PEG-Ce 6 nanomicelles for imaging and treatment of cancer.
In addition, PDT was not shown to render any appreciable toxicity.
This work presents a theranostic platform based on polymer nanomicelles
with great potential in multimodality imaging-guided photodynamic
cancer therapy
Discovery of 6āFluoro-5ā(<i>R</i>)ā(3ā(<i>S</i>)ā(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4<i>H</i>)āyl)-2-methylphenyl)-2ā(<i>S</i>)ā(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydroā1<i>H</i>ācarbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Brutonās Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers
Bruton's tyrosine
kinase (BTK), a nonreceptor tyrosine kinase,
is a member of the Tec family of kinases. BTK plays an essential role
in B cell receptor (BCR)-mediated signaling as well as FcĪ³ receptor
signaling in monocytes and FcĪµ receptor signaling in mast cells
and basophils, all of which have been implicated in the pathophysiology
of autoimmune disease. As a result, inhibition of BTK is anticipated
to provide an effective strategy for the clinical treatment of autoimmune
diseases such as lupus and rheumatoid arthritis. This article details
the structureāactivity relationships (SAR) leading to a novel
series of highly potent and selective carbazole and tetrahydrocarbazole
based, reversible inhibitors of BTK. Of particular interest is that
two atropisomeric centers were rotationally locked to provide a single,
stable atropisomer, resulting in enhanced potency and selectivity
as well as a reduction in safety liabilities. With significantly enhanced
potency and selectivity, excellent in vivo properties and efficacy,
and a very desirable tolerability and safety profile, <b>14f</b> (BMS-986142) was advanced into clinical studies
Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3āKinase Ī“ (PI3KĪ“) Inhibitor for the Treatment of Immunological Disorders
PI3KĪ“ plays an important role
controlling immune cell function and has therefore been identified
as a potential target for the treatment of immunological disorders.
This article highlights our work toward the identification of a potent,
selective, and efficacious PI3KĪ“ inhibitor. Through careful
SAR, the successful replacement of a polar pyrazole group by a simple
chloro or trifluoromethyl group led to improved Caco-2 permeability,
reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity
profile while maintaining potency in the CD69 hWB assay. The optimization
of the aryl substitution then identified a 4ā²-CN group that
improved the human/rodent correlation in microsomal metabolic stability.
Our lead molecule is very potent in PK/PD assays and highly efficacious
in a mouse collagen-induced arthritis model