Degradable Microneedle Patch with Photothermal-Promoted Bacteria-Infected Wound Healing and Microenvironment Remodeling.

Bacteria-infected wound healing is one of the most challenging issues in health management that is attracting worldwide concerns. Despite great achievements with antibiotics, emergence of antibiotic-resistance retarded the wound healing process and also led to severe outcomes. Exploration of novel antibiotics together with amelioration of wound healing efficacy is desirable. Herein, a degradable microneedle patch (AAZH@MNs) was fabricated through incorporating near-infrared light responsive photothermal agents for sustained bacteria killing and prevention of biofilm formation. In addition, the antibacterial microneedle patch could even remold the microenvironment of bacteria-infected wounds through an antibacterial effect, significantly facilitating the wound healing process.

Fluorescent naphthalimide boronates as theranostics: structural investigations, confocal fluorescence and multiphoton fluorescence lifetime imaging microscopy in living cells.

New design and synthetic strategies were developed to generate functional phenyl boronic acid (BA)-based fluorescent probes incorporating the 1,8-naphthalimide (NI) tag. This fluorescent core was anchored onto the BA unit through small organic linkers consisting of nitrogen groups which can arrest, and internally stabilise the phenyl-boronate units. The newly synthesised fluorophores were characterised spectroscopically by NMR spectroscopy and mass spectrometry and evaluated for their ability to bind to a naturally occurring polysaccharide, ß-d-glucan in DMSO and simultaneously as act as in vitro cell imaging reagents. The uptake of these new NI-boronic acid derivatives was studied living cancer cells (HeLa, PC-3) in the presence, and absence, of ß-d-glucan. Time-correlated single-photon counting (TCSPC) of DMSO solutions and two-photon fluorescence-lifetime imaging microscopy (FLIM) techniques allowed an insight into the probes' interaction with their environment. Their cellular uptake and distributions were imaged using laser scanning confocal fluorescence microscopy under single- and two-photon excitation regimes (λmax 910 nm). FLIM facilitated the estimation of the impact of the probe's cellular surroundings using the fluorophore lifetime. The extent to which this was mediated by the ß-d-glucan was visualised by 2-photon FLIM in living cells. The fluorescence lifetime observed under a range of temperatures varied appreciably, indicating that changes in the environment can be sensed by these probes. In all cases, the cellular membrane penetration of these new probes was remarkable even under variable temperature conditions and localisation was widely concentrated in the cellular cytoplasm, without specific organelle trapping: we conclude that these new probes show promise for cellular imaging in living cancer cells.

Single Doping for Triple Functions: Integrated Theranostic Nanoplatforms for Multimodal Image-Guided Tumor Therapy.

Accurate location and efficient treatment of diseases by multifunctional nanoplatforms are appealing but face great challenges. Theranostic agents through the physical combination of different functional nanoparticles are demonstrated to be effective. Yet, the complicated biological environment often leads to ambiguous fates of each agent, which fails to keep the behaviors of imaging and therapeutic components in a simultaneous manner. Herein, "integrated" theranostic NPs, Gd-doped CuWO4 (CWG) with strong near-infrared (808 nm) absorption, the longest absorption peak of reported CuWO4 , located in the biological transparent window, are constructed. The single doping of trace amount of Gd not only endows them with a distinguished magnetic resonance imaging capability (r1 = 12.01 mM-1 s-1 ), but also concurrently imposes great effect on the valence states of matrix ion (Cu), as evidenced by theoretical calculation results. The charge distribution shift of Cu would facilitate ·OH generation, beneficial for chemodynamic therapy (CDT). Moreover, CWG NPs display remarkable photoacoustic (PA) and computed tomography (CT) imaging capabilities (S = 10.33 HU mM-1 ). Such integrated theranostics afford a paradigm for multimodal imaging-guided synergistic therapy with all-in-one single nanoparticle.

A trade-off between ligand coating and crystallinity of Gd-doped ultrasmall CeO2 for improving relaxivity.

A Gd-doped ultrasmall CeO2 contrast agent was prepared with high longitudinal relaxivity (r1 = 10.1 mM-1 s-1, 7.0 T) through rationally regulating the crystallinity and surface coatings, providing a new paradigm for optimizing MRI performance. Moreover, responsive photoacoustic imaging (PAI) was established via tumor microenvironment-triggered oxidation, affording dual-modal imaging.

A Novel Strategy to Improve Tumor Targeting of Hydrophilic Drugs and Nanoparticles for Imaging Guided Synergetic Therapy.

The fast renal clearance of hydrophilic small molecular anticancer drugs and ultrasmall nanoparticles (NPs) results in the low utilization rate and certain side effects, thus improving the tumor targeting is highly desired but faces great challenges. A novel and general ß-cyclodextrin (CD) aggregation-induced assembly strategy to fabricate doxorubicin (DOX) and CD-coated NPs (such as Au) co-encapsulated pH-responsive nanocomposites (NCs) is proposed. By adding DOX×HCl and reducing pH in a reversed microemulsion system, hydrophilic CD-coated AuNPs rapidly assemble into large NCs. Then in situ polymerization of dopamine and sequentially coordinating with Cu2+ on the surface of NCs provide extra weak acid responsiveness, chemodynamic therapy (CDT), and improved biocompatibility as well as stability. The subsequent tumor microenvironment responsive dissociation notably improves their passive tumor targeting, bioavailability, imaging, and therapeutic capabilities, as well as facilitates their internalization by tumor cells and metabolic clearance, thereby reducing side effects. The combination of polymerized dopamine and assembled AuNPs reinforces photothermal capability, thus further boosting CDT through thermally amplifying Cu-catalyzed Fenton-like reaction. Both in vitro and in vivo studies confirm the desirable outcomes of these NCs as photoacoustic imaging guided trimodal (thermally enhanced CDT, photothermal therapy, and chemotherapy) synergistic tumor treatment agents with minimal systemic toxicity.

Efficacy and safety of PARP inhibitors in the treatment of BRCA-mutated breast cancer: an updated systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Poly-ADP-ribose polymerase inhibitors (PARPis) have emerged as a new class of therapeutic agents for breast cancer patients with breast cancer susceptibility gene (BRCA) mutations. However, the efficacy and toxicity of PARPis have not been clearly established. METHODS: This study comprehensively evaluated the efficacy and safety of PARPis in patients with BRCA-mutated breast cancer. Online databases were systematically searched, and six clinical trials were included. The primary endpoint of efficacy was progression-free survival (PFS), whereas the secondary endpoints were overall survival (OS) and objective response rate (ORR). Additionally, we assessed the safety of PARPis. RESULTS: The results of the meta-analysis showed that PARPis can effectively improve the PFS and OS in patients compared with the control group. The pooled HR (PARPi vs control groups) was 0.63 (95% CI, 0.55 - 0.73) and 0.83 (95% CI, 0.73 to -0.95) for PFS and OS, respectively. In safety, PARPis demonstrated controllable adverse reactions. There were no significant differences in overall AEs or grade ≥3 AEs between the PARP inhibitor and control arms. CONCLUSIONS: Our results confirm the efficacy and safety of PARPis in patients with BRCA-mutated breast cancer, and more specifically clarify the efficacy of PARPis alone or in combination with other chemotherapy drugs. [Figure: see text].

Single-Atom Gd Nanoprobes for Self-Confirmative MRI with Robust Stability.

Gadolinium (Gd)-based complexes are extensively utilized as contrast agents (CAs) in magnetic resonance imaging (MRI), yet, suffer from potential safety concerns and poor tumor targeting. Herein, as a mimic of Gd complex, single-atom Gd nanoprobes with r1 and r2 values of 34.2 and 80.1 mM-1 s-1 (far higher than that of commercial Gd CAs) at 3 T are constructed, which possessed T1 /T2 dual-mode MRI with excellent stability and good tumor targeting ability. Specifically, single-atom Gd is anchored on nitrogen-doped carbon matrix (Gd-Nx C) through spatial-confinement method, which is further subjected to controllable chemical etching to afford fully etched bowl-shape Gd-Nx C (feGd-Nx C) with hydrophilic properties and defined coordination structure, similar to commercial Gd complex. Such nanostructures not only maximized the Gd3+ site exposure, but also are suitable for self-confirmative diagnosis through one probe with dual-mode MRI. Moreover, the strong electron localization and interaction between Gd and N atoms afforded feGd-Nx C excellent kinetic inertness and thermal stability (no significant Gd3+ leaching is observed even incubated with Cu2+ and Zn2+ for two months), providing a creative design protocol for MRI CAs.

Minimalistic Artificial Catalysts with Esterase-Like Activity from Multivalent Nanofibers Formed by the Self-Assembly of Dipeptides.

Imitating and incorporating the multiple key structural features observed in natural enzymes into a minimalistic molecule to develop an artificial catalyst with outstanding catalytic efficiency is an attractive topic for chemists. Herein, we designed and synthesized one class of minimalistic dipeptide molecules containing a terminal -SH group and a terminal His-Phe dipeptide head linked by a hydrophobic alkyl chain with different lengths, marked as HS-C n+1-His-Phe (n = 4, 7, 11, 15, and 17; n + 1 represents the carbon atom number of the alkyl chain). The His (-imidazole), Phe (-CO2 -) moieties, the terminal -SH group, and a long hydrophobic alkyl chain were found to have important contributions to achieve high binding ability leading to outstanding absolute catalytic efficiency (k cat/K M) toward the hydrolysis reactions of carboxylic ester substrates.

Coordination-Driven Self-Assembly of Iron Oxide Nanoparticles for Tumor Microenvironment-Responsive Magnetic Resonance Imaging.

Accurate diagnosis of diseases located in deep tissues is always challenging. The "always-on" probe often leads to false-positive signals due to nonspecific interaction of nanoprobes. Thus, stimuli-responsive nanoprobes are highly desirable, which, however, require complicated surface modification so as to achieve trigger-induced signal changes. Here pH-triggered switchable magnetic resonance imaging (MRI) nanoprobes were constructed by coordination-driven self-assembly of monodispersed iron oxide nanoparticles (MIONPs) with simple amino acid derivatives, which displayed typical T2-weighted MRI features, yet, were turned into T1-weighted MRI under slightly acidic conditions at the tumor site. The dynamic assembly and disassembly properties of MIONPs afford T2/T1 switchable contrast imaging, enabling selective "turn-on" signals at the tumor site with high specificity.

Dual-Channel Recognition of Human Serum Albumin and Glutathione by Fluorescent Probes with Site-Dependent Responsive Features.

Design of chemical probes with high specificity and responses are particularly intriguing. In this work, a fluorescent probe (M-OH-SO3) with dual-channel spectral responses toward human serum albumin (HSA) is presented. By employing dinitrobenzenesulfonate as a recognition site as well as a fluorescence quencher, probe M-OH-SO3 displayed weak fluorescence, which, nevertheless, exhibits extensive yellow (575 nm) and red (660 nm) fluorescence emissions toward HSA under excitations at 400 and 500 nm, respectively. Interestingly, M-OH-SO3 displayed the best performance toward HSA with distinctly higher selectivity than that of its counterparts M-SO3, M-H-SO3, and M-F-SO3, which were prepared simply by modulating the functional group at the ortho position of the dicyanoisophorone core. Molecular docking results revealed that M-OH-SO3 possesses the lowest binding energy among the tested derivatives and accordingly the strongest binding affinity. Probe M-OH-SO3 showed a good linear relationship toward HSA in a range of 0.5-18 µM with a limit of detection of 35 nM. Cell imaging results demonstrated that probe M-OH-SO3 could visualize the variation HSA levels in hepatocarcinoma cells. In addition, probe M-OH-SO3 could also be employed for the recognition of glutathione through the cleavage of the dinitrobenzenesulfonate group along with an enhancement of emission at 575 nm. The site-dependent properties inspired a novel paradigm for design of fluorescent probes with optimized selectivity and responses.

Stepwise-Enhanced Tumor Targeting of Near-Infrared Emissive Au Nanoclusters with High Quantum Yields and Long-Term Stability.

We developed an in situ coordination-driven spatially confined strategy for preparing near-infrared emissive gold nanoclusters encapsulated by fluorinated polymers (AuNCs@PF, λmax = 810 nm) with good stability and high quantum yields (27.7%), far higher than those previously reported for NIR AuNCs (>800 nm). Based on the stepwise enhancements including long blood circulation-induced passive tumor targeting, fluoro-enhanced tumor permeation, and tumor microenvironment (weak acid)-induced aggregation retention in cells, these AuNCs demonstrated bright and stable NIR fluorescence imaging ability in tumors. Additionally, the AuNCs@PF were capable of fluorine magnetic resonance imaging and computed tomographic imaging. The multimodal imaging of tumor-bearing mice clearly implied the potential of AuNCs@PF in biomedical fields.

Design of Fluorinated Probes for Versatile Surface Functionalization and 19 F Magnetic Resonance Imaging.

The development of multifunctional nanoplatforms for bioimaging and therapy has attracted extensive attention in recent decades. As an emerging magnetic resonance imaging (MRI) technique, 19 F MRI effectively complements the limit of 1 H MRI owing to trace amount of 19 F atoms existing in the human body, affording high specificity. In this work, a novel molecule (CFO) containing hydrophilic fluorine fragments was synthesized using amino acids as starting materials, which could self-assemble into small nanoprobes via hydrophobic interactions of oleic acid moiety. The as-prepared nanoprobes displayed good relaxation performances thanks to the carboxylate group and sulfoxide group nearby. The nanoprobes successfully demonstrated its capacity for in-vivo 19 F MRI. In addition, CFO could be used as a general fluorine labeling agent for surface functionalization of nanoparticles, which provided a universal method for constructing water-soluble multifunctional nanoplatforms.

In Situ Fabrication of Nanoprobes for 19F Magnetic Resonance and Photoacoustic Imaging-Guided Tumor Therapy.

It is challenging to fabricate multimodal imaging nanoprobes with high penetration depth and long blood circulation. Herein, we present multifunctional fluorinated nanoprobes (CFPP NPs) containing in situ formed copper chalcogenide nanoparticles for 19F magnetic resonance imaging (MRI) and photoacoustic imaging (PAI). The formed hydrophilic copper chalcogenide nanoassemblies demonstrated easy excretion stemming from facile disassembly, enhanced photothermal ability, and novel localized surface plasmon resonance (LSPR) absorption (centered at 1064 nm) in the "biological transparent" region. Both 19F MRI and PAI render these CFPP NPs suitable for multimodal imaging with high penetration depth and low background. Moreover, the chemo-photothermal synergistic therapy results suggest great potential in multimodal nanoprobes for imaging-guided tumor therapy applications.

19F-Grafted Fluorescent Carbonized Polymer Dots for Dual-Mode Imaging.

Dual-modal imaging systems could provide complementary information by taking advantage of each imaging modality. Herein, a fluorescence and 19F magnetic resonance imaging nanoprobe was developed through preparation of 19F-grafted fluorescent carbonized polymer dots (FCPDs). Both fluorescence and 19F nuclear magnetic resonance intensities of these FCPDs can be modulated by controlling the carbonization processes. The strong yellow fluorescence renders these FCPDs capable of cell fluorescence imaging. The in vitro and in vivo assessments demonstrated that the as-prepared FCPDs were suitable for 19F magnetic resonance imaging (19F MRI), which would provide great potential for biological imaging and early diagnosis applications. Moreover, this fabrication strategy offers a new protocol for 19F MRI nanoprobe design.

Selective Ligand Sensitization of Lanthanide Nanoparticles for Multilevel Information Encryption with Excellent Durability.

Durable and multilevel information encryption technology has been of great importance in recent decades. Here, an inkjet printer-adaptable invisible ink was prepared with lanthanide nanoparticles, and optical decoding of information could only be achieved when specific ligand dipicolinic acid was utilized in the presence of UV illumination. In addition, the proposed protocols displayed long shelf life (>one year) and excellent durability even at harsh conditions such as in the presence of strong acids (1 M HCl) and alkalis (1 M NaOH). Meanwhile, such invisible inks could be further employed on a soft matrix via screen-printing, holding great potential for practical applications.

Intratumoral Glutathione Activatable Nanoprobes for Fluorescence and 19F Magnetic Resonance Turn-On Imaging.

Tumor microenvironment turn-on nanoprobes that could specifically detect the occurrence of diseases possess great potential in early diagnosis. Here, a GSH activated nanoprobe was designed for fluorescence and 19F magnetic resonance (MR) dual-modal turn-on imaging of tumors. Specifically, fluorescence AgInS2 quantum dots (QDs for fluorescence imaging) were co-encapsulated with perfluoro-15-crown-5-ether (P19FCE for19F MRI) by amphiphilic polymers and further coated with in situ formed manganese dioxide (MnO2) nanoshells, which served as efficient fluorescence and 19F MR quenchers due to energy transfer and paramagnetic relaxation effects, respectively. The over-expressed GSH in tumors would decompose the MnO2 nanoshells, resulting in remarkable enhancement of both fluorescence and 19F MRI signals of the nanoprobes, accordingly lighting up the tumor site.

Fluorinated ZnFeIII Hollow Metal-Organic Framework as a 19F NMR Probe for Highly Sensitive and Selective Detection of Hydrogen Sulfide.

Hydrogen sulfide (H2S) is considered as a highly toxic environmental pollutant and an important signal transmitter in physiological processes, and the selective and reliable detection of H2S is of great concern and remains challenging. Herein, we report a smart sensitive "off-on" 19F NMR sensor for H2S by partially introducing a fluorinated ligand to construct a hollow dual metal-organic framework (MOF) nanosystem, F-ZnFeIII hMOF, in which the fluorinated ligand acts as the 19F signal source but is initially quenched due to the strong paramagnetic relaxation enhancement (PRE) effect from neighboring Fe3+ nodes. Upon exposure to sulfide ions, reduction of Fe3+ to Fe2+ is specifically triggered, which attenuates PRE efficiency, thus turning on the 19F NMR signal. The unique hollow MOF architecture benefits the mobility of 19F atoms, thereby improving the response sensitivity. Meanwhile, the desirable H2S-sorption feature and appropriate redox potential of Fe3+/Fe2+ account for the favorable selectivity. The increase in the 19F signal is linear with the concentration of sulfide in the range of 20 to 150 µM with a detection limit of 2.8 µM. The probe is well demonstrated by analyzing H2S in complex matrixes such as biological and foodstuff samples.

A Versatile Strategy for Surface Functionalization of Hydrophobic Nanoparticle by Boronic Acid Modified Polymerizable Diacetylene Derivatives.

The flourishing advancements in nanotechnology significantly boost their application in biomedical fields. Whereas, inorganic nanomaterials are normally prepared and capped with hydrophobic ligands, which require essential surface modification to increase their biocompatibility and endow extra functions. Phenylboronic acid derivatives have long been known for its capacity for selective recognition of saccharides. Herein, we demonstrated a versatile surface modification strategy to directly convert hydrophobic inorganic nanocrystals into water-dispersible and targeting nanocomposites by employing boronic acid modified photo-polymerizable 10,12-pentacosadiynoicacid and further explore its potentials in selective cancer cell imaging.

Regulating locations of active sites: a novel strategy to greatly improve the stability of PtAu electrocatalysts.

Durability improvement of Pt-based catalysts is crucial to fuel cells. Herein, we report a highly stable PtAu nanocatalyst via rationally regulating locations of Pt and Au active sites.

19F MRI Nanoprobes for the Turn-On Detection of Phospholipase A2 with a Low Background.

The highly sensitive detection and imaging of enzymatic activities in vivo could provide effective information about biological functions for monitoring the process of disease and evaluating the effect of therapy. 19F magnetic resonance imaging (MRI) has attracted wide interest because of its deep tissue imaging capability and negligible endogenous background interference, which are suitable for the visualization of enzymatic activities in vivo, but the fabrication of this probe faces challenges. Here, we report nanoprobes with turn-on 19F MRI for sensing the activity of phospholipase A2 (PLA2). These nanoprobes are composed of Gd3+-exchanged NaYF4:Yb3+/Er3+ upconversion luminescent nanoparticles grafted with perfluoro-15-crown-5-ether (PFCE) as the hydrophobic core with a phospholipid shell in which the 19F MRI signal of PFCE is obviously quenched by adjacent Gd3+. The shielded 19F MRI signal of these nanoprobes is then turned on by the nanoprobe dissolution stemming from phospholipid hydrolysis by PLA2 and increases linearly along with the increment of PLA2 in the range of 5.0-200 U/L. Apart from the in vitro detection of PLA2 by 19F NMR, these nanoprobes show great potential for both the in vivo 19F MRI sensing of PLA2 and activity screening of PLA2 inhibitors with a high signal-to-noise ratio and a high penetration depth.