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Aurora kinase B (AURKB) is an attractive and potential molecular target for cervical cancer therapy. To date, a variety of AURKB inhibitors are developed to suppress cervical tumors. Nevertheless, direct use of these small molecule inhibitors may cause severe side effects to patients, limiting their further clinical applications. Herein, a rationally designed hydrogelator Nap‐Phe‐Phe‐Arg‐Arg‐Lys‐Ser‐OH (S) is employed to co‐assemble AZD1152‐HQPA (AZD, an AURKB inhibitor) to develop an AURKB‐responsive hydrogel Gel S/AZD for enhanced cervical tumor suppression. Upon AURKB activation, hydrogelator S in Gel S/AZD evolves into its hydrophilic phosphate Nap‐Phe‐Phe‐Arg‐Arg‐Lys‐Ser(H2PO3)‐OH (Sp), triggering the disassembly of Gel S/AZD to release AZD in a sustained manner. Cell assays reveal that AURKB‐responsive release of AZD from Gel S/AZD potently induces the growth arrest and apoptosis of cervical cancer cells by downregulating the expression level of AURKB downstream protein phospho‐histone H3 (pH3). In vivo studies demonstrate that compared with free AZD, Gel S/AZD shows a superior tumor suppressive effect in orthotropic cervical tumor models. It is envisioned that the Gel S/AZD might be applied in clinic cervical cancer treatment in the near future. [ABSTRACT FROM AUTHOR]

Mimetic enzymes are devised as alternates or supplements of natural enzymes in broad fields but regulating their activities in a switchable manner remains challenging. Herein, we proposed an enzymatic self-assembly/disassembly strategy to address this issue. A peptide molecule NapFFEYIH (YH) was rationally designed which, after self-assembling into nanofibers, lined up the histidine moieties to form active hydrolysis centers for mimicking hydrolase activity. Enzymatic dephosphorylation of NapF-FEYpIH (YpH) by alkaline phosphatase to yield YH also turned "ON" the hydrolase activity. In turn, phosphorylation of YH by phosphokinase epidermal growth factor receptor to yield YpH disassembled the nanofibers and thus turned the activity "OFF". As such, the "ON"/"OFF" of the mimetic hydrolase activities could be regulated under physiological conditions through ALP/EGFR-mediated self-assembly/disassembly of histidine nanofibers. This work provides a feasible strategy for the on-demand fabrication of artificial enzymes with controllable and superior activities. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a major cause of death and disability worldwide. The poor drug delivery to cerebral ischemic regions remains a challenging issue for ischemic stroke treatment. Curcumin (Cur) and edaravone (EDV) show remarkable therapeutic effects on ischemic stroke. However, the short half‐life and poor aqueous solubility limit their application for long‐term and effective neuroprotection. Cur and EDV with a well‐studied hydrogelator Nap‐Phe‐Phe‐Tyr‐OH (NapFFY) is co‐assembled to prepare a novel supramolecular peptide hydrogel EDV/Cur/NapFFY, which can improve their bioavailability and transport the hydrophobic drugs to ischemic sites precisely by local administration. In vitro release test demonstrate that co‐assembly with NapFFY enables continuous release of Cur and EDV for about two weeks. Animal studies found that EDV/Cur/NapFFY hydrogel can effectively promote brain plasticity and enhance the functional recovery on the photothrombotic mouse model. Overall, the work reveales the great application potential of supramolecular peptide hydrogel delivery system EDV/Cur/NapFFY in promoting repair and recovery of ischemic stroke. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus (S. aureus) is able to hide within host cells to escape immune clearance and antibiotic action, causing life‐threatening infections. To boost the therapeutic efficacy of antibiotics, new intracellular delivery approaches are urgently needed. Herein, by rational design of an adamantane (Ada)‐containing antibiotic‐peptide precursor Ada‐Gly‐Tyr‐Val‐Ala‐Asp‐Cys(StBu)‐Lys(Ciprofloxacin)‐CBT (Cip‐CBT‐Ada), we propose a strategy of tandem guest‐host‐receptor recognitions to precisely guide ciprofloxacin to eliminate intracellular S. aureus. Via guest‐host recognition, Cip‐CBT‐Ada is decorated with a β‐cyclodextrin‐heptamannoside (CD‐M) derivative to yield Cip‐CBT‐Ada/CD‐M, which is able to target mannose receptor‐overexpressing macrophages via multivalent ligand‐receptor recognition. After uptake, Cip‐CBT‐Ada/CD‐M undergoes caspase‐1 (an overexpressed enzyme during S. aureus infection)‐initiated CBT‐Cys click reaction to self‐assemble into ciprofloxacin nanoparticle Nano‐Cip. In vitro and in vivo experiments demonstrate that, compared with ciprofloxacin or Cip‐CBT‐Ada, Cip‐CBT‐Ada/CD‐M shows superior intracellular bacteria elimination and inflammation alleviation efficiency in S. aureus‐infected RAW264.7 cells and mouse infection models, respectively. This work provides a supramolecular platform of tandem guest‐host‐receptor recognitions to precisely guide antibiotics to eliminate intracellular S. aureus infection efficiently. [ABSTRACT FROM AUTHOR]

Derived from the D‐luciferin regeneration pathway in firefly body, the click condensation reaction between 2‐cyanobenzothiazole (CBT) and D‐cysteine (Cys) (CBT‐Cys click reaction) possesses unique advantages, including superior biocompatibility, high second order reaction rate, and metal‐free mild conditions, emerging as a powerful bioorthogonal tool for a variety of chemical biological applications. Moreover, owing to its programmable controllability (e.g., pH, reduction, or enzyme), CBT‐Cys click reaction is exploited to fabricate stimuli‐activatable imaging probes with self‐assembling behaviors in physiological context. At stimuli‐rich pathological lesions of interest, these probes undergo CBT‐Cys click reaction to form cyclic dimers/oligomers or linear polymers, and further self‐assemble into nanostructures. The in situ formed nanostructures promote the selective accumulation and retention of imaging agent cargos at pathological lesions, thus enabling precise and enhanced in vivo imaging of diseases (especially tumors). To address the significance and recent breakthroughs of smart CBT‐Cys probes for enhanced optical imaging of tumors/other diseases, we herein propose this mini‐review, in which advances (particularly in recent 5 years) and potential challenges (or chances) in this field are emphasized. [ABSTRACT FROM AUTHOR]

Azide-alkyne cycloaddition reaction is a very common organic reaction to synthesize nitrogen-containing heterocycles. Once catalyzed by Cu(I) or Ru(II), it turns out to be a click reaction and thus is widely applied in chemical biology for labeling. However, besides their poor regioselectivity towards this reaction, these metal ions are not biologically friendly. Hence, it is an urgent need to develop a metal-free azide–alkyne cycloaddition reaction for biomedical applications. In this work, we found that, in the absence of metal ions, supramolecular self-assembly in an aqueous solution could realize this reaction with excellent regioselectivity. Nap-Phe-Phe-Lys(azido)-OH firstly self-assembled into nanofibers. Then, Nap-Phe-Phe-Gly(alkynyl)-OH at equivalent concentration approached to react with the assembly to yield the cycloaddition product Nap-Phe-Phe-Lys(triazole)-Gly-Phe-Phe-Nap to form nanoribbons. Due to space confinement effect, the product was obtained with excellent regioselectivity. Employing the excellent properties of supramolecular self-assembly, we are applying this strategy to realize more reactions without metal ion catalysis. Metal-free versions of azide–alkyne cycloadditions could find widespread applications in biomedical contexts. Here, the authors report an assembly-driven, regioselective azide–alkyne cycloaddition. [ABSTRACT FROM AUTHOR]

Salt‐inducible kinase 2 (SIK2) is a promising target for ovarian cancer therapy due to its critical role in tumorigenesis and progression. Currently available SIK2 inhibitors have shown remarkable therapeutic effects on ovarian cancers in preclinical studies. However, direct administration of the SIK2 inhibitors may bring significant off‐target effect, limiting their clinical applications. In this work, by rational design of a hydrogelator Nap‐Phe‐Phe‐Glu‐Glu‐Leu‐Tyr‐Arg‐Thr‐Gln‐Ser‐Ser‐Ser‐Asn‐Leu‐OH (Nap‐S) to coassemble a SIK2 inhibitor HG‐9‐91‐01 (HG), a SIK2‐responsive supramolecular hydrogel (Gel Nap‐S+HG) for local administration and SIK2‐responsive release of HG is reported to efficiently suppress ovarian cancer metastasis. Under the activation of SIK2 overexpressed in ovarian cancers, Nap‐S in the hydrogel is phosphorylated to yield hydrophilic Nap‐Phe‐Phe‐Glu‐Glu‐Leu‐Tyr‐Arg‐Thr‐Gln‐Ser(H2PO3)‐Ser‐Ser‐Asn‐Leu (Nap‐Sp), triggering the disassembly of the hydrogel and a responsive release of the inhibitor. Cell experiments indicate that sustained release of HG from Gel Nap‐S+HG induce a prominent therapeutic effect on cancer cells by inhibiting SIK2 and phosphorylation of their downstream signaling molecules. Animal experiments demonstrate that, compared with those tumor model mice treated with free HG, Gel Nap‐S+HG‐treatment mice show an enhanced inhibition on ovarian tumor growth and metastasis. It is anticipated that the Gel Nap‐S+HG can be applied for ovarian cancer therapy in clinic in the near future. [ABSTRACT FROM AUTHOR]

Alkaline phosphatase (ALP) and γ-glutamyltranspeptidase (GGT) are regarded as two important biomarkers in several human cancers. There are many probes for ALP or GGT detection but no probe was reported to sense the activity of both ALP and GGT in vitro or in vivo. Herein, a bioluminescent probe P-Bz-Luc was designed for realizing sensitive and specific tumor imaging via the co-cleavage of ALP and GGT. In solution experiments showed that an excellent linear relationship was found between the bioluminescence signal of the P-Bz-Luc solution and the enzyme concentration at limits of detection of 0.172 for ALP and 0.634 U L−1 for GGT. Eventually, the BL probe P-Bz-Luc was successfully applied for sensitive imaging of the ALP and GGT co-overexpressed fLuc-231 breast cancer cells and tumors, with the help of the coordination cleavage of P-Bz-Luc by ALP and GGT. [ABSTRACT FROM AUTHOR]

This study was undertaken to report the swift, facile and convenient synthesis of novel hydrazones obtained by condensation reaction between 2-Amino-3-formylchromone and hydrazine derivatives. Various characterization techniques such as MALDI Mass, FTIR, 1HNMR and 13CNMR spectrum analysis was done to determine the chemical structure of these novel six hydrazones. Furthermore, UV-Vis and fluorescence spectra was studied to calculate λmax and εmax. These hydrazones are quite useful for their facile synthesis and chemical structure. Such hydrazones require separate clinical research to find their applications in biomedical fields. [ABSTRACT FROM AUTHOR]

Cathepsin B (CTSB) is a lysosomal protease that is overexpressed in the early stage of many cancer types. Precise evaluation of CTSB expression in vivo may provide a promising method for the early diagnosis of cancers. By virtue of the high‐resolution PA imaging modality, a "smart" photoacoustic (PA) probe Cypate‐CBT, which can self‐assemble to cypate‐containing nanoparticles in response to abundant GSH and CTSB inside tumor cells, was developed for the sensitive and specific detection of CTSB activity. Compared with unmodified Cypate, our probe Cypate‐CBT exhibited a 4.9‐fold or 4.7‐fold PA signal enhancement in CTSB‐overexpressing MDA‐MB‐231 cancer cells or tumors, respectively, revealing intracellular accumulation of the probe after CTSB‐initiated self‐assembly. We expect Cypate‐CBT to be employed as an effective PA imaging agent for clinical diagnosis of cancer at early stages. [ABSTRACT FROM AUTHOR]