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1.
Nano Lett ; 23(13): 6178-6183, 2023 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-37363812

RESUMEN

Apoptosis, with a hallmark of upregulated protease Caspase-3, has been frequently imaged with various probes to reveal the therapeutic efficiencies of different drugs. However, activatable molecular probes with programmable self-assembling behaviors that enable enhanced T1-weighted magnetic resonance imaging (MRI) of apoptosis remain scarce. Herein, taking advantage of a CBT-Cys click reaction, we rationally designed a Caspase-3-activatable self-assembling probe Ac-Asp-Glu-Val-Asp-Cys(StBu)-Lys(DOTA(Gd))-CBT (DEVDCS-Gd-CBT) for apoptosis imaging in vivo. After Caspase-3 cleavage in apoptotic cells, DEVDCS-Gd-CBT underwent CBT-Cys click reaction to form a cyclic dimer, which self-assembled into Gd nanoparticles. With this probe, enhanced T1-weighted MR images of apoptosis were achieved at low magnetic fields in vitro, in cis-dichlorodiamineplatinum-induced apoptotic cells and in tail-amputation-simulated apoptotic zebrafish. We anticipate that the smart probe DEVDCS-Gd-CBT could be applied for T1-weighted MRI of apoptosis-related diseases in the clinic in the future.


Asunto(s)
Gadolinio , Nanopartículas , Animales , Caspasa 3 , Pez Cebra , Imagen por Resonancia Magnética/métodos , Apoptosis , Medios de Contraste
2.
J Am Chem Soc ; 145(14): 7918-7930, 2023 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-36987560

RESUMEN

Oral squamous cell carcinoma (OSCC) is the most common oral cancer, having high recurrence and metastasis features. In addition to surgery, photodynamic therapy (PDT) is considered as another effective approach for OSCC treatment. The water solubility of currently available PDT photosensitizers (PSs) is poor, lowering their singlet oxygen (1O2) yield and consequent PDT efficiency. Strategies of PS assembly have been reported to increase 1O2 yield, but it is still possible to further enhance PDT efficiency. In this work, we utilized apoptosis to amplify the assembly of porphyrin nanofibers for enhanced PDT of OSCC. A water-soluble porphyrin derivative, Ac-Asp-Glu-Val-Asp-Asp-TPP (Ac-DEVDD-TPP), was designed for this purpose. Upon caspase-3 (Casp3, an activated enzyme during apoptosis) cleavage and laser irradiation, Ac-DEVDD-TPP was converted to D-TPP, which spontaneously self-assembled into porphyrin nanofibers, accompanied by 1.4-fold and 2.1-fold 1O2 generations in vitro and in cells, respectively. The as-formed porphyrin nanofiber induced efficient cell apoptosis and pyroptosis. In vivo experiments demonstrated that, compared with the scrambled control compound Ac-DEDVD-TPP, Ac-DEVDD-TPP led to 6.2-fold and 1.3-fold expressions of Casp3 in subcutaneous and orthotopic oral tumor models, respectively, and significantly suppressed the tumors. We envision that our strategy of apoptosis-amplified porphyrin assembly might be applied for OSCC treatment in the clinic in the near future.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de la Boca , Nanofibras , Fotoquimioterapia , Porfirinas , Humanos , Porfirinas/farmacología , Caspasa 3 , Apoptosis , Agua
3.
J Am Chem Soc ; 145(50): 27748-27756, 2023 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-38052046

RESUMEN

Aggregation-induced emission (AIE) enables "Turn-On" imaging generally through single aggregation of the AIE luminogen (AIEgen). Dual aggregrations of the AIEgen might further enhance the imaging intensity and the consequent sensitivity. Herein, we rationally designed a near-infrared (NIR) AIEgen Ac-Trp-Glu-His-Asp-Cys(StBu)-Pra(QMT)-CBT (QMT-CBT) which, upon caspase1 (Cas1) activation, underwent a CBT-Cys click reaction to form cyclic dimers QMT-Dimer (the first aggregation) and assembled into nanoparticles (the second aggregation), turning the AIE signal "on" for enhanced imaging of Alzheimer's disease (AD). Molecular dynamics simulations validated that the fluorogen QMT in QMT-NPs stacked much tighter with each other than in the single aggregates of the control compound Ac-Trp-Glu-His-Asp-Cys(tBu)-Pra(QMT)-CBT (QMT-CBT-Ctrl). Dual aggregations of QMT rendered 1.9-, 1.7-, and 1.4-fold enhanced fluorescence intensities of its single aggregation in vitro, in cells, and in a living AD mouse model, respectively. We anticipate this smart fluorogen to be used for sensitive diagnosis of AD in the clinic in the near future.


Asunto(s)
Enfermedad de Alzheimer , Nanopartículas , Animales , Ratones , Enfermedad de Alzheimer/diagnóstico por imagen , Imagen Óptica/métodos , Simulación de Dinámica Molecular , Colorantes Fluorescentes
4.
Anal Chem ; 95(14): 5839-5842, 2023 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-36946513

RESUMEN

Featured with molecule-level data encryption, molecular keypad locks show attractive merits in information security. Most of the previous multiple-input locks use fluorescence as output but are impeded by inefficient/labile prequenching or highly synthetic complexity/difficulty of the fluorophore-containing processor molecules. We herein propose a facile three-input molecular keypad lock, which is simple in synthesis and label free but capable of in situ generation of a fluorescent moiety (dityrosine) for background-free fluorescence readout. A nonfluorescent ("Locked") tyrosine derivate zYpc was easily synthesized as the processor. The correct "password" (i.e., UV → ALP → TYR, ABC) stepwise converted zYpc to a dityrosine-containing product, exhibiting a bright blue fluorescence output ("Open"). In contrast, wrongly permutated inputs failed to open this lock. This device shows potential to be extended as a more advanced keypad lock with better security.

5.
Nano Lett ; 22(16): 6782-6786, 2022 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-35943287

RESUMEN

Emissive excimers, which are formed by planar polycyclic aromatic fluorophores (e.g., coumarin), enable high contrast tumor imaging. However, it is still challenging to "turn on" excimer fluorescence in physiological dilute solutions. The biocompatible CBT-Cys click condensation reaction enables both intra- and intermolecular aggregations of the as-loaded fluorophores on the probe molecules, which may promote the generation of emissive excimers in a synergistic manner. As a proof-of-concept, we herein design a fluorescence probe Cbz-Gly-Pro-Cys(StBu)-Lys(coumarin)-CBT (Cbz-GPC(StBu)K(Cou)-CBT), which can be activated by FAP-α under tumor-inherent reduction conditions, undergo a CBT-Cys click reaction, and self-assemble into coumarin nanoparticle Cou-CBT-NP to "turn on" the excimer fluorescence. In vitro and in vivo studies validate that this "smart" probe realizes efficient excimer fluorescence imaging of FAP-α-overexpressed tumor cells with high contrast and enhanced accumulation, respectively. We anticipate that this probe can be applied for diagnosis of FAP-α-related diseases in the clinic in near future.


Asunto(s)
Nanopartículas , Neoplasias , Cumarinas , Colorantes Fluorescentes , Humanos , Neoplasias/diagnóstico por imagen , Imagen Óptica/métodos
6.
Angew Chem Int Ed Engl ; 62(32): e202306427, 2023 08 07.
Artículo en Inglés | MEDLINE | ID: mdl-37347163

RESUMEN

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 ß-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.


Asunto(s)
Ciclodextrinas , Infecciones Estafilocócicas , Animales , Ratones , Ciprofloxacina/farmacología , Ciprofloxacina/uso terapéutico , Staphylococcus aureus , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología
7.
J Am Chem Soc ; 144(26): 11897-11910, 2022 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-35731698

RESUMEN

Metastasis-induced high mortality of cancers urgently demands new approaches to simultaneously inhibit primary tumor metastasis and distant tumor growth. Herein, by rational design of a trident molecule Nap-Phe-Phe-Lys(SA-CPT)-Lys(SA-HCQ)-Tyr(H2PO3)-OH (Nap-CPT-HCQ-Yp) with three functional "spears" (i.e., a phosphotyrosine motif for enzymatic self-assembly, camptothecin (CPT) motif for chemotherapy, and hydroxychloroquine (HCQ) motif for autophagy inhibition) and nanobrush-nanoparticle-nanofiber transition property, we propose a novel strategy of intracellular enzymatic nanofiber formation and synergistic autophagy inhibition-enhanced chemotherapy and immunotherapy for spatial suppression of tumor metastasis. Under sequential alkaline phosphatase catalysis and carboxylesterase hydrolysis, Nap-CPT-HCQ-Yp undergoes nanobrush-nanoparticle-nanofiber transition, accompanied by the releases of CPT and HCQ. The formed intracellular nanofibers effectively inhibit the metastasis and invasion behaviors of cancer cells. Meanwhile, the released CPT and HCQ synergistically induce a prominent therapeutic effect through autophagy inhibition-enhanced chemotherapy. Furthermore, chemotherapy of Nap-CPT-HCQ-Yp enhances immunogenic cell death, resulting in the activation of toxic T-cells. Finally, a combination of checkpoint blockade therapy and Nap-CPT-HCQ-Yp-mediated chemotherapy elicits systemic antitumor immunity, thereby achieving efficient inhibitions of primary tumors as well as distant tumors in a breast tumor model. Our work offers a simple and feasible strategy for the design of "smart" multifunctional prodrugs to spatially suppress tumor metastasis.


Asunto(s)
Neoplasias de la Mama , Nanofibras , Nanopartículas , Profármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Camptotecina/farmacología , Camptotecina/uso terapéutico , Línea Celular Tumoral , Femenino , Humanos , Hidroxicloroquina/farmacología , Hidroxicloroquina/uso terapéutico , Profármacos/uso terapéutico
8.
Anal Chem ; 93(3): 1636-1642, 2021 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-33381969

RESUMEN

Development of fluorescence probes for highly accurate detection of cancer-related enzyme activity is important in early cancer diagnosis. Herein, we report a Golgi-targeting and dual-color "Turn-On" probe Q-RVRR-DCM for imaging furin with high spatial precision. By integrating the principles of Förster resonance energy transfer and intramolecular charge transfer, the probe was designed to be non-fluorescent. Upon furin cleavage, Q-RVRR-DCM was converted into Q-RVRR and DCM-NH2, turning the dual fluorescence color "On" at 420 and 640 nm without spectral cross-talk. In furin-overexpressing HCT116 cells, Q-RVRR-DCM showed not only furin-specific, dual-color "Turn-On" fluorescence but also superior colocalization with a Golgi tracker than the single-color "Turn-On" probe RVRR-DCM. We envision that, with the excellent properties of Golgi-targeting and dual fluorescence color "Turn-On", our furin probe Q-RVRR-DCM could be applied for accurate early diagnosis of cancer in the near future.


Asunto(s)
Color , Colorantes Fluorescentes/química , Furina/análisis , Aparato de Golgi/química , Furina/metabolismo , Células HCT116 , Humanos , Microscopía Fluorescente , Estructura Molecular , Imagen Óptica , Células Tumorales Cultivadas
9.
Angew Chem Int Ed Engl ; 58(31): 10631-10634, 2019 07 29.
Artículo en Inglés | MEDLINE | ID: mdl-31167041

RESUMEN

Antimicrobial drug resistance demands novel approaches for improving the efficacy of antibiotics, especially against Gram-negative bacteria. Herein, we report that conjugating a diglycine (GG) to an antibiotic prodrug drastically accelerates intrabacterial ester-bond hydrolysis required for activating the antibiotic. Specifically, the attachment of GG to chloramphenicol succinate (CLsu) generates CLsuGG, which exhibits about an order of magnitude higher inhibitory efficacy than CLsu against Escherichia coli. Further studies reveal that CLsuGG undergoes rapid hydrolysis, catalyzed by intrabacterial esterases (e.g., BioH and YjfP), to generate chloramphenicol (CL) in E. coli. Importantly, the conjugate exhibits lower cytotoxicity to bone marrow stromal cells than CL. Structural analogues of CLsuGG indicate that the conjugation of GG to an antibiotic prodrug is an effective strategy for accelerating enzymatic prodrug hydrolysis and enhancing the antibacterial efficacy of antibiotics.


Asunto(s)
Antibacterianos/farmacología , Escherichia coli/efectos de los fármacos , Glicilglicina/farmacología , Antibacterianos/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Glicilglicina/química , Células HEK293 , Células Hep G2 , Humanos , Hidrólisis , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad
10.
Langmuir ; 31(22): 6172-8, 2015 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-25986051

RESUMEN

The protein binding capability of biomaterial surfaces can significantly affect subsequent biological responses, and appropriate ligand presentation is often required to guarantee the best functions. Herein, a new facile method for regulating this capability by varying the localized and average ligand density is presented. Binding between lysine and plasminogen relevant to a fibrinolysis system was chosen as a model. We integrated different lysine-modified ß-cyclodextrin (ß-CD) derivatives onto bioinert copolymer brushes via host-guest interactions. The localized and average lysine density can be conveniently modulated by changing the lysine valency on ß-CD scaffolds and by diluting lysine-persubstituted ß-CD with pure ß-CD, respectively. Both the plasminogen adsorption and the plasminogen binding affinity were enhanced by lysine-persubstituted ß-CD compared with those of lysine-monosubstituted ß-CD, which is possibly due to the higher localized lysine density and the multivalent binding of plasminogen on lysine-persubstituted ß-CD surfaces. With a change in the ratio of lysine-persubstituted ß-CD to ß-CD, the average lysine density can be tuned, leading to the linear regulation of the adsorption of plasminogen on surfaces.


Asunto(s)
Lisina/metabolismo , Plasminógeno/metabolismo , beta-Ciclodextrinas/metabolismo , Sitios de Unión , Ligandos , Lisina/química , Estructura Molecular , Plasminógeno/química , Propiedades de Superficie , beta-Ciclodextrinas/química
11.
Nanoscale ; 16(7): 3211-3225, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38288668

RESUMEN

Bacterial infections, especially antibiotic-resistant ones, remain a major threat to human health. Advances in nanotechnology have led to the development of numerous antimicrobial nanomaterials. Among them, in situ peptide assemblies, formed by biomarker-triggered self-assembly of peptide-based building blocks, have received increasing attention due to their unique merits of good spatiotemporal controllability and excellent disease accumulation and retention. In recent years, a variety of "turn on" imaging probes and activatable antibacterial agents based on in situ peptide assemblies have been developed, providing promising alternatives for the treatment and diagnosis of bacterial infections. In this review, we introduce representative design strategies for in situ peptide assemblies and highlight the bacterial infection imaging and treatment applications of these supramolecular materials. Besides, current challenges in this field are proposed.


Asunto(s)
Infecciones Bacterianas , Nanoestructuras , Humanos , Péptidos/uso terapéutico , Péptidos/química , Nanoestructuras/química , Nanotecnología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones Bacterianas/diagnóstico por imagen , Infecciones Bacterianas/tratamiento farmacológico
12.
Biosens Bioelectron ; 255: 116207, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38554575

RESUMEN

Near-infrared (NIR) aggregation induced-emission luminogens (AIEgens) circumvent the noisome aggregation-caused quenching (ACQ) effect in physiological milieu, thus holding high promise for real-time and sensitive imaging of biomarkers in vivo. ß-Galactosidase (ß-Gal) is a biomarker for primary ovarian carcinoma, but current AIEgens for ß-Gal sensing display emissions in the visible region and have not been applied in vivo. We herein propose an NIR AIEgen QM-TPA-Gal and applied it for imaging ß-Gal activity in vitro and in ovarian tumor model. After being internalized by ovarian cancer cells (e.g., SKOV3), the hydrophilic nonfluorescent QM-TPA-Gal undergoes hydrolyzation by ß-Gal to yield hydrophobic QM-TPA-OH, which subsequently aggregates into nanoparticles to turn NIR fluorescence "on" through the AIE mechanism. In vitro experimental results indicate that QM-TPA-Gal has a sensitive and selective response to ß-Gal with a limit of detection (LOD) of 0.21 U/mL. Molecular docking simulation confirms that QM-TPA-Gal has a good binding ability with ß-Gal to allow efficient hydrolysis. Furthermore, QM-TPA-Gal is successfully applied for ß-Gal imaging in SKOV3 cell and SKOV3-bearing living mouse models. It is anticipated that QM-TPA-Gal could be applied for early diagnosis of ovarian cancers or other ß-Gal-associated diseases in near future.


Asunto(s)
Técnicas Biosensibles , Neoplasias Ováricas , Animales , Humanos , Ratones , Femenino , Colorantes Fluorescentes/química , Simulación del Acoplamiento Molecular , Neoplasias Ováricas/diagnóstico por imagen , Imagen Óptica , beta-Galactosidasa/química , beta-Galactosidasa/metabolismo
13.
Nanoscale ; 16(24): 11538-11541, 2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38841880

RESUMEN

Aggregation-induced emission luminogens (AIEgens) enable highly sensitive and in situ visualization of sulfatase to benefit the early diagnosis of breast cancer (BC), but current sulfatase AIEgens always emit visible light (<650 nm). Herein, a near-infrared (NIR) AIEgen QMT-SFA is developed for sulfatase imaging in vivo. Hydrophilic QMT-SFA is cleaved by sulfatase to yield hydrophobic QMT-OH, which subsequently aggregates into nanoparticles to turn the AIE fluorescence "on", enabling sensitive sulfatase imaging in 4T1 cells and mouse models.


Asunto(s)
Neoplasias de la Mama , Sulfatasas , Animales , Femenino , Ratones , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Sulfatasas/metabolismo , Humanos , Colorantes Fluorescentes/química , Ratones Endogámicos BALB C , Nanopartículas/química , Rayos Infrarrojos , Ratones Desnudos
14.
Adv Healthc Mater ; 13(10): e2303472, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37985951

RESUMEN

Current molecular photoacoustic (PA) probes are designed with either stimulus-turned "on" or assembly-enhanced signals to trace biological analytes/events. PA probes based on the nature-derived click reaction between 2-cyano-6-aminobenzothiazole (CBT) and cysteine (Cys) (i.e., CBT-Cys click reaction) possess both "turn-on" and "enhanced" PA signals; and thus, should have higher sensitivity. Nevertheless, such PA probes, particularly those for sensitive imaging of tumor hypoxia, remain scarce. Herein, a PA probe NI-Cys(StBu)-Dap(IR780)-CBT (NI-C-CBT) is rationally designed, which after being internalized by hypoxic tumor cells, is cleaved by nitroreductase under the reduction condition to yield cyclic dimer C-CBT-Dimer to turn the PA signal "ON" and subsequently assembled into nanoparticles C-CBT-NPs with additionally enhanced PA signal ("Enhanced"). NI-C-CBT exhibits 1.7-fold "ON" and 3.2-fold overall "Enhanced" PA signals in vitro. Moreover, it provides 1.9-fold and 2.8-fold overall enhanced PA signals for tumor hypoxia imaging in HeLa cells and HeLa tumor-bearing mice, respectively. This strategy is expected to be widely applied to design more "smart" PA probes for sensitive imaging of important biological events in vivo in near future.


Asunto(s)
Nanopartículas , Técnicas Fotoacústicas , Humanos , Animales , Ratones , Células HeLa , Hipoxia Tumoral , Diagnóstico por Imagen , Nitrorreductasas , Técnicas Fotoacústicas/métodos
15.
Adv Mater ; 36(21): e2308504, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38546279

RESUMEN

Anexelekto (AXL) is an attractive molecular target for ovarian cancer therapy because of its important role in ovarian cancer initiation and progression. To date, several AXL inhibitors have entered clinical trials for the treatment of ovarian cancer. However, the disadvantages of low AXL affinity and severe off-target toxicity of these inhibitors limit their further clinical applications. Herein, by rational design of a nonapeptide derivative Nap-Phe-Phe-Glu-Ile-Arg-Leu-Arg-Phe-Lys (Nap-IR), a strategy of in situ nanofiber formation is proposed to suppress ovarian cancer growth. After administration, Nap-IR specifically targets overexpressed AXL on ovarian cancer cell membranes and undergoes a receptor-instructed nanoparticle-to-nanofiber transition. In vivo and in vitro experiments demonstrate that in situ formed Nap-IR nanofibers efficiently induce apoptosis of ovarian cancer cells by blocking AXL activation and disrupting subsequent downstream signaling events. Remarkably, Nap-IR can synergistically enhance the anticancer effect of cisplatin against HO8910 ovarian tumors. It is anticipated that the Nap-IR can be applied in clinical ovarian cancer therapy in the near future.


Asunto(s)
Tirosina Quinasa del Receptor Axl , Péptidos y Proteínas de Señalización Intercelular , Nanofibras , Neoplasias Ováricas , Proteínas Proto-Oncogénicas , Proteínas Tirosina Quinasas Receptoras , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Humanos , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Nanofibras/química , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Línea Celular Tumoral , Animales , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Oligopéptidos/química , Oligopéptidos/farmacología , Ratones , Unión Proteica , Cisplatino/farmacología , Cisplatino/química
16.
Adv Mater ; 36(23): e2312153, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38444205

RESUMEN

The presence of bacteria in tumor results in chemotherapeutic drug resistance and weakens the immune response in colorectal cancer. To overcome bacterium-induced chemotherapeutic drug resistance and potentiate antitumor immunity, herein a novel molecule Biotin-Lys(SA-Cip-OH)-Lys(SA-CPT)-Phe-Phe-Nap (Biotin-Cip-CPT-Nap) is rationally designed containing four functional motifs (i.e., a biotin motif for targeting, Phe-Phe(-Nap) motif for self-assembly, ciprofloxacin derivative (Cip-OH) motif for antibacterial effect, and camptothecin (CPT) motif for chemotherapy). Using the designed molecule, a novel strategy of intracellular enzymatic nanofiber formation and synergistic antibacterium-enhanced chemotherapy and immunotherapy is achieved. Under endocytosis mediated by highly expressed biotin receptor in colorectal cancer cell membrane and the catalysis of highly expressed carboxylesterase in the cytoplasm, this novel molecule can be transformed into Biotin-Nap, which self-assembled into nanofibers. Meanwhile, antibiotic Cip-OH and chemotherapeutic drug CPT are released, overcoming bacterium-induced drug resistance and enhancing the therapeutic efficacy of immunotherapy towards colorectal cancer. This work offers a feasible strategy for the design of novel multifunctional prodrugs to improve the efficiency of colorectal cancer treatment.


Asunto(s)
Antineoplásicos , Neoplasias Colorrectales , Profármacos , Profármacos/química , Profármacos/farmacología , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Animales , Inmunoterapia , Péptidos/química , Péptidos/farmacología , Camptotecina/farmacología , Camptotecina/química , Antibacterianos/farmacología , Antibacterianos/química , Ratones , Nanofibras/química , Ciprofloxacina/farmacología , Ciprofloxacina/química , Liberación de Fármacos , Biotina/química
17.
Nat Commun ; 14(1): 3935, 2023 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-37402737

RESUMEN

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.

18.
Adv Healthc Mater ; 12(18): e2203283, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36880480

RESUMEN

Staphylococcus aureus (S. aureus) remains a leading cause of bacterial infections. However, eradication of S. aureus infections with common antibiotics is increasingly difficult due to outbreaks of drug resistance. Therefore, new antibiotic classes and antibacterial strategies are urgently in demand. Herein, it is shown that an adamantane-peptide conjugate, upon dephosphorylation by alkaline phosphatase (ALP) constitutively expressed on S. aureus, generates fibrous assemblies in situ to combat S. aureus infection. By attaching adamantane to a phosphorylated tetrapeptide Nap-Phe-Phe-Lys-Tyr(H2 PO3 )-OH, the rationally designed adamantane-peptide conjugate Nap-Phe-Phe-Lys(Ada)-Tyr(H2 PO3 )-OH (Nap-FYp-Ada) is obtained. Upon bacterial ALP activation, Nap-FYp-Ada is dephosphorylated and self-assembles into nanofibers on the surface of S. aureus. As revealed by cell assays, the assemblies of adamantane-peptide conjugates interact with cell lipid membrane and thereby disrupt membrane integrity to kill S. aureus. Animal experiments further demonstrate the excellent potential of Nap-FYp-Ada in the treatment of S. aureus infection in vivo. This work provides an alternative approach to design antimicrobial agents.


Asunto(s)
Antiinfecciosos , Infecciones Estafilocócicas , Animales , Staphylococcus aureus/metabolismo , Péptidos/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Antibacterianos/farmacología , Fosfatasa Alcalina/metabolismo , Pruebas de Sensibilidad Microbiana
19.
Adv Sci (Weinh) ; 9(22): e2202260, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35618488

RESUMEN

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(H2 PO3 )-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.


Asunto(s)
Hidrogeles , Neoplasias Ováricas , Secuencia de Aminoácidos , Animales , Femenino , Humanos , Ratones , Neoplasias Ováricas/tratamiento farmacológico , Fragmentos de Péptidos
20.
Adv Healthc Mater ; 11(14): e2200453, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35521978

RESUMEN

Direct, noninvasive, and real-time imaging of Staphylococcus aureus (S. aureus) infection is of great value for quick diagnosis of related disease in clinic, but remains challenging. Herein, employing a rationally designed near-infrared fluorescence probe Cys(StB u)-EDA-Thioketal-Lys(Cy5.5)-CBT (TK-CBT) and a CBT-Cys click reaction, the fluorescence-quenched nanoparticles TK-CBT-NPs are facilely prepared. Upon oxidation by the abundant reactive oxygen species in S. aureus-infected macrophages, TK-CBT-NPs are fractured, turning the fluorescence "on" for imaging infections in vitro and in vivo. Specifically, TK-CBT-NPs show a 6.1-fold fluorescence imaging signal enhancement of the macrophages that are infected by S. aureus for 20 h in vitro. At 4 h postinjection, TK-CBT-NPs show a 2.8-fold fluorescence imaging signal enhancement of the sites in mice that are infected by S. aureus for 24 h. It is anticipated that TK-CBT-NPs could be applied for diagnosis of S. aureus infections in clinic in the near future.


Asunto(s)
Nanopartículas , Infecciones Estafilocócicas , Animales , Ratones , Imagen Óptica/métodos , Especies Reactivas de Oxígeno , Infecciones Estafilocócicas/diagnóstico por imagen , Staphylococcus aureus
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