An all-in-one tetrazine reagent for cysteine-selective labeling and bioorthogonal activable prodrug construction.

The prodrug design strategy offers a potent solution for improving therapeutic index and expanding drug targets. However, current prodrug activation designs are mainly responsive to endogenous stimuli, resulting in unintended drug release and systemic toxicity. In this study, we introduce 3-vinyl-6-oxymethyl-tetrazine (voTz) as an all-in-one reagent for modular preparation of tetrazine-caged prodrugs and chemoselective labeling peptides to produce bioorthogonal activable peptide-prodrug conjugates. These stable prodrugs can selectively bind to target cells, facilitating cellular uptake. Subsequent bioorthogonal cleavage reactions trigger prodrug activation, significantly boosting potency against tumor cells while maintaining exceptional off-target safety for normal cells. In vivo studies demonstrate the therapeutic efficacy and safety of this prodrug design approach. Given the broad applicability of functional groups and labeling versatility with voTz, we foresee that this strategy will offer a versatile solution to enhance the therapeutic range of cytotoxic agents and facilitate the development of bioorthogonal activatable biopharmaceuticals and biomaterials.

UV absorption enhanced polydopamine coating.

Mussel-inspired polydopamine (PDA) coatings have gained significant attention in various fields, including biomedicine, energy, detection, and UV protection, owing to their versatile and promising properties. Among these properties, UV shielding stands out as a key feature of PDA coatings. Nevertheless, the current methods for tuning the UV-shielding properties of PDA coatings are quite limited, and only rely on thickness adjustment, which might involve additional issues like color and visible light transmittance to the coating layer. In this study, we propose a facile and modular approach to enhance the UV absorption of PDA coatings by incorporating thiol-heterocycle (TH) derivatives. Both pre- and post-modification strategies can effectively impede the formation of conjugated structures within PDA, leading to enhanced UV absorption within the PDA layers. More importantly, these strategies can improve the UV absorption of PDA coatings while reducing the visible light absorption. Furthermore, this method enabled efficient regulation of the UV absorption of PDA coatings by altering the ring type (benzene ring or pyridine ring) and substituent on the ring (methoxyl group or hydrogen atom). These PDA coatings with enhanced UV absorption demonstrate great promise for applications in UV protection, antibacterial activity, wound healing and dye degradation.

Pretargeted radiotherapy and synergistic treatment of metastatic, castration-resistant prostate cancer using cross-linked, PSMA-targeted lipoic acid nanoparticles.

Metastatic castration-resistant prostate cancer (CRPC) is a currently incurable disease associated with high mortality. Novel therapeutic approaches for CRPC are urgently needed to improve prognosis. In this study, we developed cross-linked, PSMA-targeted lipoic acid nanoparticles (cPLANPs), which can interact with transmembrane glycoprotein to accumulate inside prostate cancer cells, where they upregulate caspase-3, downregulate anti-apoptotic B-cell lymphoma-2 (BCL-2), and thereby induce apoptosis. The trans-cyclooctene (TCO) decoration on cPLANPs acts as a bioorthogonal handle allowing pretargeted single-photon emission computed tomography and radiotherapy, which revealed significantly enhanced tumor accumulation and minimal off-target toxicity in our experiments. The developed strategy showed a strong synergistic anti-cancer effect in vivo, with a tumor inhibition rate of up to 95.6% after 14 days of treatment. Our results suggest the potential of combining bioorthogonal pretargeted radiotherapy with suitable PSMA-targeted nanoparticles for the treatment of metastatic CRPC.

Waste Tea-Derived Theabrownins for Solar-Driven Steam Generation.

Solar-driven seawater desalination has been considered an effective and sustainable solution to mitigate the global freshwater crisis. However, the substantial cost associated with photothermal materials for evaporator fabrication still hinders large-scale manufacturing for practical applications. Herein, we successfully obtained high yields of theabrownins (TB), which were oxidation polymerization products of polyphenols from waste and inferior tea leaves using a liquid-state fermentation strategy. Subsequently, a series of photothermal complexes were prepared based on the metal-phenolic networks assembled from TB and metal ions (Fe(III), Cu(II), Ni(II), and Zn(II)). Also, the screened TB@Fe(III) complexes were directly coated on a hydrophilic poly(vinylidene fluoride) (PVDF) membrane to construct the solar evaporation device (TB@Fe(III)@PVDF), which not only demonstrated superior light absorption property and notable hydrophilicity but also achieved a high water evaporation rate of 1.59 kg m-2 h-1 and a steam generation efficiency of 90% under 1 sun irradiation. More importantly, its long-term stability and exceptionally low production cost enabled an important step toward the possibility of large-scale practical applications. We believe that this study holds the potential to pave the way for the development of sustainable and cost-effective photothermal materials, offering new avenues for utilization of agriculture resource waste and solar-driven water remediation.

Robust and Multifunctional Therapeutic Nanoparticles against Peritonitis-Induced Sepsis.

Apart from bacterial growth and endotoxin generation, the excessive production of reactive radicals linked with sepsis also has a substantial impact on triggering an inflammatory response and further treatment failure. Hence, the rational design and fabrication of robust and multifunctional nanoparticles (NPs) present a viable means of overcoming this dilemma. In this study, we used antibiotic polymyxin B (PMB) and antioxidant natural polyphenolic protocatechualdehyde (PCA) to construct robust and multifunctional NPs for sepsis treatment, leveraging the rich chemistries of PCA. The PMB release profile from the NPs demonstrated pH-responsive behavior, which allowed the NPs to exhibit effective bacterial killing and radical scavenging properties. Data from in vitro cells stimulated with H2O2 and lipopolysaccharide (LPS) showed the multifunctionalities of NPs, including intracellular reactive oxygen species (ROS) scavenging, elimination of the bacterial toxin LPS, inhibiting macrophage M1 polarization, and anti-inflammation capabilities. Additionally, in vivo studies further demonstrated that NPs could increase the effectiveness of sepsis treatment by lowering the bacterial survival ratio, the expression of the oxidative marker malondialdehyde (MDA), and the expression of inflammatory cytokine TNF-α. Overall, this work provides ideas of using those robust and multifunctional therapeutic NPs toward enhanced sepsis therapy efficiency.

A bioorthogonal cell sorting strategy for isolation of desired cell phenotypes.

Here we describe a cost-effective and simplified cell sorting method using tetrazine bioorthogonal chemistry. We successfully isolated SKOV3 cells from complex mixtures, demonstrating efficacy in separating mouse lymphocytes expressing interferon and HeLa cells expressing virally transduced green fluorescent protein post-infection.

Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism.

Glioblastoma is the most lethal primary brain tumor with glioblastoma stem cells (GSCs) atop a cellular hierarchy. GSCs often reside in a perivascular niche, where they receive maintenance cues from endothelial cells, but the role of heterogeneous endothelial cell populations remains unresolved. Here, we show that lymphatic endothelial-like cells (LECs), while previously unrecognized in brain parenchyma, are present in glioblastomas and promote growth of CCR7-positive GSCs through CCL21 secretion. Disruption of CCL21-CCR7 paracrine communication between LECs and GSCs inhibited GSC proliferation and growth. LEC-derived CCL21 induced KAT5-mediated acetylation of HMGCS1 on K273 in GSCs to enhance HMGCS1 protein stability. HMGCS1 promoted cholesterol synthesis in GSCs, favorable for tumor growth. Expression of the CCL21-CCR7 axis correlated with KAT5 expression and HMGCS1K273 acetylation in glioblastoma specimens, informing patient outcome. Collectively, glioblastomas contain previously unrecognized LECs that promote the molecular crosstalk between endothelial and tumor cells, offering potentially alternative therapeutic strategies.

Tetrazine-Isonitrile Bioorthogonal Fluorogenic Reactions Enable Multiplex Labeling and Wash-Free Bioimaging of Live Cells.

Developing fluorogenic probes for simultaneous live cell labeling of multiple targets is crucial for understanding complex cellular events. The emerging [4+1] cycloaddition between tetrazine and isonitriles holds promise as a bioorthogonal tool, yet existing tetrazine probes lack reactivity and fluorogenicity. Here, we present the development of a series of tetrazine-functionalized bioorthogonal probes. By incorporating pyrazole adducts into the fluorophore scaffolds, the post-reacted probes displayed remarkable fluorescence turn-on ratios, up to 3184-fold. Moreover, these modifications are generalizable to various fluorophores, enabling a broad emission range from 473 to 659 nm. Quantum chemical calculations further elucidate the turn-on mechanisms. These probes enable the simultaneous labeling of multiple targets in live cells, without the need for a washing step. Consequently, our findings pave the way for advanced multiplex imaging and detection techniques for cellular studies.

Bioorthogonal Cleavage of Tetrazine-Caged Ethers and Esters Triggered by trans-Cyclooctene.

In this study, we report the bioorthogonal cleavage of physiologically stable methylene tetrazines bearing an ether or ester linkage in the presence of trans-cyclooctene. Based on this approach, molecules with phenol or carboxylic acid moieties were efficiently released in a controlled manner, which can be effectively applied in living cells. We expect this bioorthogonal cleavage approach can be applied to several biomedical applications, including the development of antibody-drug conjugates, pretargeted prodrug release, and protein activation.

Versatile polyphenolic platforms in regulating cell biology.

Polyphenolic materials are a class of fascinating and versatile bioinspired materials for biointerfacial engineering. In particular, due to the presence of active chemical groups, a series of unique physicochemical properties become accessible and tunable of the as-prepared polyphenolic platforms, which could delicately regulate the cell activities via cell-material contact-dependent interactions. More interestingly, polyphenols could also affect the cell behaviors via cell-material contact-independent manner, which arise due to their intrinsically functional characteristics (e.g., antioxidant and photothermal behaviors). As such, a comprehensive understanding on the relationship between material properties and desired biomedical applications, as well as the underlying mechanism at the cellular and molecular level would provide material design principles and accelerate the lab-to-clinic translation of polyphenolic platforms. In this review, we firstly give a brief overview of cell hallmarks governed by surrounding cues, followed by the introduction of polyphenolic material engineering strategies. Subsequently, a detailed discussion on cell-polyphenols contact-dependent interfacial interaction and contact-independent interaction was also carefully provided. Lastly, their biomedical applications were elaborated. We believe that this review could provide guidances for the rational material design of multifunctional polyphenols and extend their application window.

Tuning the Physicochemical Properties of BODIPY for Bioimaging via meso-Amino Acylation.

A series of BODIPY probes with a wide emission range were prepared via aminoacylation at the meso-position. Functional moieties were also introduced to induce bathochromic shifts in emission, improve water solubility, increase Stokes shifts, and construct bioorthogonal turn-on probes. The developed analogues were successfully used in live-cell imaging, suggesting that the described strategy can be used to prepare probes with improved bioimaging potential.

Overcoming Spectral Dependence: A General Strategy for Developing Far-Red and Near-Infrared Ultra-Fluorogenic Tetrazine Bioorthogonal Probes.

Bioorthogonal fluorogenic dyes are indispensable tools in wash-free bioimaging of specific biological targets. However, the fluorogenicity of existing tetrazine-based bioorthogonal probes deteriorates as the emission wavelength shifts towards the NIR window, greatly limiting their applications in live cells and tissues. Herein, we report a generalizable molecular design strategy to construct ultra-fluorogenic dyes via a simple substitution at the meso-positions of various far-red and NIR fluorophores. Our probes demonstrate significant fluorescence turn-on ratios (102 -103 -fold) in the range 586-806 nm. These results will greatly expand the applications of bioorthogonal chemistry in NIR bioimaging and biosensing.

Isonitrile induced bioorthogonal activation of fluorophores and mutually orthogonal cleavage in live cells.

Fluorophores with different emission wavelengths were efficiently quenched by a tert-butyl terminated tetrazylmethyl group and activated by an isonitrile-tetrazine click-to-release reaction. Nucleic acid templated chemistry significantly accelerated this bioorthogonal cleavage. Moreover, two mutually orthogonal fluorogenic cleavage reactions were simultaneously conducted in live cells for the first time.

Reduced polydopamine nanoparticles incorporated oxidized dextran/chitosan hybrid hydrogels with enhanced antioxidative and antibacterial properties for accelerated wound healing.

Hydrogels with antioxidative and antibacterial properties have emerged as potential dressings for accelerated wound healing. Herein, a series of reduced polydopamine nanoparticles (rPDA NPs) incorporated oxidized dextran/chitosan hybrid hydrogels have been designed for wound healing due to their excellent antioxidative property and antibacterial activity. The physicochemical properties as well as the antioxidative activities of the hydrogels were carefully characterized. The results demonstrated rPDA NPs have better antioxidative activity than the untreated PDA NPs. And the rPDA NPs incorporated oxidized dextran/chitosan hybrid hydrogels had excellent antioxidative properties to protect cells against external oxidative stress. Besides, the hydrogels also showed antibacterial ability to protect the wound against infections. In vitro and in vivo investigations concluded that rPDA NPs incorporated oxidized dextran/chitosan hybrid hydrogels could be served as an effective dressing for accelerated wound healing.

Concise Synthesis of Functionalized Cyclobutene Analogues for Bioorthogonal Tetrazine Ligation.

Novel bioorthogonal tools enable the development of new biomedical applications. Here we report the concise synthesis of a series of aryl-functionalized cyclobutene analogues using commercially available starting materials. Our study demonstrates that cyclobutene acts as a small, strained dienophile to generate stable substrates suitable for bioorthogonal tetrazine ligation.

A General Strategy to Design Highly Fluorogenic Far-Red and Near-Infrared Tetrazine Bioorthogonal Probes.

Highly fluorogenic tetrazine bioorthogonal probes emitting at near-infrared wavelengths are in strong demand for biomedical imaging applications. Herein, we have developed a strategy for forming a palette of novel Huaxi-Fluor probes in situ, whose fluorescence increases hundreds of times upon forming the bioorthogonal reaction product, pyridazine. The resulting probes show large Stokes shifts and high quantum yields. Manipulating the conjugate length and pull-push strength in the fluorophore skeleton allows the emission wavelength to be fine-tuned from 556 to 728 nm. The highly photo-stable and biocompatible probes are suitable for visualizing organelles in live cells without a washing step and for imaging of tumors in live small animals to depths of 500 µm by two-photon excitation.

Recent advances in development of dendritic polymer-based nanomedicines for cancer diagnosis.

Dendritic polymers have highly branched three-dimensional architectures, the fourth type apart from linear, cross-linked, and branched one. They possess not only a large number of terminal functional units and interior cavities, but also a low viscosity with weak or no entanglement. These features endow them with great potential in various biomedicine applications, including drug delivery, gene therapy, tissue engineering, immunoassay and bioimaging. Most review articles related to bio-related applications of dendritic polymers focus on their drug or gene delivery, while very few of them are devoted to their function as cancer diagnosis agents, which are essential for cancer treatment. In this review, we will provide comprehensive insights into various dendritic polymer-based cancer diagnosis agents. Their classification and preparation are presented for readers to have a precise understanding of dendritic polymers. On account of physical/chemical properties of dendritic polymers and biological properties of cancer, we will suggest a few design strategies for constructing dendritic polymer-based diagnosis agents, such as active or passive targeting strategies, imaging reporters-incorporating strategies, and/or internal stimuli-responsive degradable/enhanced imaging strategies. Their recent applications in in vitro diagnosis of cancer cells or exosomes and in vivo diagnosis of primary and metastasis tumor sites with the aid of single/multiple imaging modalities will be discussed in great detail. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > in vivo Nanodiagnostics and Imaging Diagnostic Tools > in vitro Nanoparticle-Based Sensing.

The Therapeutic Potential of Purinergic Receptors in Alzheimer's Disease and Promising Therapeutic Modulators.

Recent studies have proven that the purinergic signaling pathway plays a key role in neurotransmission and neuromodulation, and is involved in various neurodegenerative diseases and psychiatric disorders. With the characterization of the subtypes of receptors in purinergic signaling, i.e. the P1 (adenosine), P2X (ion channel) and P2Y (G protein-coupled), more attention has been paid to the pathophysiology and therapeutic potential of purinergic signaling in the central nervous system disorders. Alzheimer's disease (AD) is a progressive and deadly neurodegenerative disease that is characterized by memory loss, cognitive impairment and dementia. However, as drug development aimed to prevent or control AD has series of failures in recent years, more researchers have focused on the neuroprotection-related mechanisms such as purinergic signaling in AD patients to find a potential cure. This article reviews the recent discoveries of purinergic signaling in AD, and summarizes the potential agents as modulators for the receptors of purinergic signaling in AD-related research and treatments. Thus, our paper provides an insight into purinergic signaling in the development of anti- AD therapies.

A Brief Introduction to Porphyrin Compounds used in Tumor Imaging and Therapies.

As a group of heterocyclic macrocycle organic natural compounds occurring universally in animal tissues and plants, porphyrins are composed of four modified pyrrole subunits. Porphyrin analogues/ derivatives possess multiple biochemical properties because of their unique structures and have been extensively investigated in cancer treatment. Studies have shown that porphyrins and their derivatives have the ability to locate tumor cells in a variety of human cancers, and these compounds not only exhibit potent therapeutic effects as photodynamic agents but also show promising properties in medicinal imaging, such as MRI, photoacoustic imaging, fluorescence imaging, and PET/SPECT imaging. This paper reviews the recent reports of porphyrin derivatives as therapeutic agents used in tumor therapies, such as sonodynamic therapy, photodynamic therapy and radiotherapy, as well as the imaging agents for multimodality tumor imaging. The limitations of porphyrin-based compounds in tumor treatments and future prospects are also summarized.