RESUMEN
Mechanoresponsive materials can harness mechanical forces to initiate molecular events and alter their physicochemical properties. Enzyme reactions, which enable diverse chemical transformations under mild conditions, have great potential as outputs of the mechanoresponse, especially in biological applications. Here, we present a hydrogel-based platform that realizes mechanotransduction to enzyme reactions through the modulation of multivalent salt-bridge interactions between a polymeric inhibitor incorporated within the gel network and an enzyme in the gel matrix. As a proof-of-concept study, two types of hydrogels were developed: BGGu-gel with ß-galactosidase and TBGu-gel with thrombin. The BGGu-gel, containing a chromogenic substrate, exhibits mechanochromism, visually mapping the mechanical load onto the gel via a colorimetric response. The TBGu-gel, containing fibrinogen as a substrate, displays self-growth, achieving enhanced mechanical strength under stress through thrombin-mediated hydrolysis of fibrinogen into fibrin, followed by the spontaneous formation of fibrin fibers as an additional gel network.
RESUMEN
Herein, we report an ATP-responsive nanoparticle (GroEL NP) whose surface is fully covered with the biomolecular machine "chaperonin protein GroEL". GroEL NP was synthesized by DNA hybridization between a gold NP with DNA strands on its surface and GroEL carrying complementary DNA strands at its apical domains. The unique structure of GroEL NP was visualized by transmission electron microscopy including under cryogenic conditions. The immobilized GroEL units retain their machine-like function and enable GroEL NP to capture denatured green fluorescent protein and release it in response to ATP. Interestingly, the ATPase activity of GroEL NP per GroEL was 4.8 and 4.0 times greater than those of precursor cys GroEL and its DNA-functionalized analogue, respectively. Finally, we confirmed that GroEL NP could be iteratively extended to double-layered ( GroEL ) 2 ${{^{({\rm GroEL}){_{2}}}}}$ NP.
Asunto(s)
Adenosina Trifosfato , Chaperoninas , Chaperoninas/metabolismo , Adenosina Trifosfato/metabolismo , Chaperonina 60/química , Pliegue de ProteínaRESUMEN
We developed a photoreactive molecular glue, BPGlue-N3, which can provide a universal strategy to enhance the efficacy of DNA aptamers by temporary-to-permanent stepwise stabilization of their conjugates with target proteins. As a proof-of-concept study, we applied BPGlue-N3 to the SL1 (DNA aptamer)/c-Met (target protein) conjugate system. BPGlue-N3 can adhere to and temporarily stabilize this aptamer/protein conjugate multivalently using its guanidinium ion (Gu+) pendants that form a salt bridge with oxyanionic moieties (e.g., carboxylate and phosphate) and benzophenone (BP) group that is highly affinitive to DNA duplexes. BPGlue-N3 is designed to carry a dual-mode photoreactivity; upon exposure to UV light, the temporarily stabilized aptamer/protein conjugate reacts with the photoexcited BP unit of adhering BPGlue-N3 and also a nitrene species, possibly generated by the BP-to-N3 energy transfer in BPGlue-N3. We confirmed that SL1, covalently conjugated with c-Met, hampered the binding of hepatocyte growth factor (HGF) onto c-Met, even when the SL1/c-Met conjugate was rinsed prior to the treatment with HGF, and suppressed cell migration caused by HGF-induced c-Met phosphorylation.
Asunto(s)
Aptámeros de Nucleótidos/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Aptámeros de Nucleótidos/química , Azidas/química , Benzofenonas/química , Línea Celular Tumoral , Movimiento Celular , Factor de Crecimiento de Hepatocito/química , Factor de Crecimiento de Hepatocito/metabolismo , Humanos , Microscopía Confocal , Fosforilación , Unión Proteica , Proteínas Proto-Oncogénicas c-met/química , Rayos UltravioletaRESUMEN
Here we report a bio-adhesive porous organic module (Glue COF) composed of hexagonally packed 1D nanopores based on a covalent organic framework. The nanopores are densely decorated with guanidinium ion (Gu+ ) pendants capable of forming salt bridges with oxyanionic species. Glue COF strongly adheres to biopolymers through multivalent salt-bridging interactions with their ubiquitous oxyanionic species. By taking advantage of its strong bio-adhesive nature, we succeeded in creating a gate that possibly opens the nanopores through a selective interaction with a reporter chemical and releases guest molecules. We chose calmodulin (CaM) as a gating component that can stably entrap a loaded guest, sulforhodamineâ B (SRB), within the nanopores (CaM COFâSRB). CaM is known to change its conformation on binding with Ca2+ ions. We confirmed that mixing CaM COFâSRB with Ca2+ resulted in the release of SRB from the nanopores, whereas the use of weakly binding Mg2+ ions resulted in a much slower release of SRB.
RESUMEN
Caspase-3 (Casp-3) is an enzyme that efficiently induces apoptosis, a form of programmed cell death. We report a dendritic molecular glue PCGlue that enables intracellular delivery of Casp-3 and its photoactivation. PCGlue carrying multiple guanidinium (Gu+) ion pendants via photocleavable linkages can tightly adhere to Casp-3 and deliver it into the cytoplasm mainly by direct penetration through the plasma membrane. Casp-3, whose surface is covered by PCGlue, is unable to interact with its cellular substrates and can therefore not induce apoptosis. However, upon exposure to UV or two-photon near-infrared (NIR) light, PCGlue is cleaved off to liberate Casp-3, triggering the apoptotic signaling cascade. This intracellular photoactivation of Casp-3 allows spatiotemporal induction of apoptosis in irradiated cells.
Asunto(s)
Caspasa 3/química , Guanidina/química , Nitrocompuestos/química , Apoptosis , Caspasa 3/metabolismo , Línea Celular Tumoral , Humanos , Rayos Infrarrojos , Estructura Molecular , Procesos Fotoquímicos , Rayos UltravioletaRESUMEN
We developed a dendritic molecular glue PCGlue-NBD that can serve universally to "turn on" protein-protein interactions (PPIs) spatiotemporally. PCGlue-NBD carrying multiple guanidinium ion (Gu+) pendants can adhere strongly to target proteins and cover their surfaces including the PPI interface regions, thereby suppressing PPIs with their receptor proteins. Upon irradiation with UV light, PCGlue-NBD on a target protein is photocleaved at butyrate-substituted nitroveratryloxycarbonyl linkages in the dendrimer framework, so that the multivalency for the adhesion is reduced. Consequently, the guest protein is liberated and becomes eligible for a PPI. We found that hepatocyte growth factor HGF, when mixed with PCGlue-NBD, lost the affinity toward its receptor c-Met. However, upon exposure of the PCGlue-NBD/HGF hybrid to light-emitting diode light (365 nm), the PCGlue-NBD molecules on HGF were photocleaved as described above, so that HGF was liberated and retrieved its intrinsic PPI affinity toward c-Met. The turn-on PPI, thus achieved for HGF and c-Met, leads to cell migration, which can be made spatiotemporally with a millimeter-scale resolution by pointwise irradiation with UV light.
Asunto(s)
4-Cloro-7-nitrobenzofurazano/farmacología , Dendrímeros/farmacología , Guanidinas/farmacología , Factor de Crecimiento de Hepatocito/metabolismo , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-met/metabolismo , 4-Cloro-7-nitrobenzofurazano/síntesis química , 4-Cloro-7-nitrobenzofurazano/efectos de la radiación , Línea Celular Tumoral , Dendrímeros/síntesis química , Dendrímeros/efectos de la radiación , Guanidinas/síntesis química , Guanidinas/efectos de la radiación , Factor de Crecimiento de Hepatocito/química , Humanos , Unión Proteica/efectos de la radiación , Proteínas Proto-Oncogénicas c-met/química , Rayos UltravioletaRESUMEN
Transferrin (Tf) is known to induce transcytosis, which is a consecutive endocytosis/exocytosis event. We developed a Tf-appended nanocaplet (TfNCâsiRNA) for the purpose of realizing siRNA delivery into deep tissues and RNA interference (RNAi) subsequently. For obtaining TfNCâsiRNA, a macromonomer (AzGu) bearing multiple guanidinium (Gu+) ion units, azide (N3) groups, and trityl (Trt)-protected thiol groups in the main chain, side chains, and termini, respectively, was newly designed. Because of a multivalent Gu+-phosphate salt-bridge interaction, AzGu can adhere to siRNA along its strand. When I2 was added to a preincubated mixture of AzGu and siRNA, oxidative polymerization of AzGu took place along the siRNA strand, affording AzNCâsiRNA, the smallest siRNA-containing reactive nanocaplet so far reported. This conjugate was converted into Glue/BPNCâsiRNA by the click reaction with a Gu+-appended bioadhesive dendron (Glue) followed by a benzophenone derivative (BP). Then, Tf was covalently immobilized onto Glue/BPNCâsiRNA by Gu+-mediated adhesion followed by photochemical reaction with BP. With the help of Tf-induced transcytosis, TfNCâsiRNA permeated deeply into a cancer spheroid, a 3D tissue model, at a depth of up to nearly 70 µm, unprecedentedly.
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Portadores de Fármacos/química , Nanoestructuras/química , ARN Interferente Pequeño/metabolismo , Esferoides Celulares/fisiología , Transferrina/química , Línea Celular Tumoral , Técnicas de Silenciamiento del Gen/métodos , Guanidinas/química , Humanos , Interferencia de ARN/fisiología , Transcitosis/fisiologíaRESUMEN
We developed dendritic caged molecular glues (CagedGlue-R) as tags for nucleus-targeted drug delivery, whose multiple guanidinium ion (Gu+) pendants are protected by an anionic photocleavable unit (butyrate-substituted nitroveratryloxycarbonyl; BANVOC). Negatively charged CagedGlue-R hardly binds to anionic biomolecules because of their electrostatic repulsion. However, upon exposure of CagedGlue-R to UV light or near-infrared (NIR) light, the BANVOC groups of CagedGlue-R are rapidly detached to yield an uncaged molecular glue (UncagedGlue-R) that carries multiple Gu+ pendants. Because Gu+ forms a salt bridge with PO4-, UncagedGlue-R tightly adheres to anionic biomolecules such as DNA and phospholipids in cell membranes by a multivalent salt-bridge formation. When tagged with CagedGlue-R, guests can be taken up into living cells via endocytosis and hide in endosomes. However, when the CagedGlue-R tag is photochemically uncaged to form UncagedGlue-R, the guests escape from the endosome and migrate into the cytoplasm followed by the cell nucleus. We demonstrated that quantum dots (QDs) tagged with CagedGlue-R can be delivered efficiently to cell nuclei eventually by irradiation with light.
Asunto(s)
Adhesivos/metabolismo , Núcleo Celular/metabolismo , Guanidina/metabolismo , Luz , Adhesivos/química , Línea Celular Tumoral , Núcleo Celular/química , Endocitosis , Endosomas/química , Endosomas/metabolismo , Guanidina/química , Humanos , Estructura Molecular , Procesos Fotoquímicos , Puntos Cuánticos/química , Puntos Cuánticos/metabolismoRESUMEN
FLNBD-BAMPEG2k, bearing a nitrobenzoxadiazole (NBD) unit and an oleyl terminus conjugated via a poly(ethylene glycol) (PEG) spacer ( Mn = 2,000), was designed to fluorescently label cell membranes by docking its hydrophobic oleyl terminus. During laser scanning microscopy in a minimal essential medium (MEM), human hepatocellular carcinoma Hep3B cells labeled with FLNBD-BAMPEG2k appeared to undergo optoporation at their plasma membrane. We confirmed this unprecedented possibility by a series of cellular uptake experiments using negatively charged and therefore membrane-impermeable quantum dots (QDs; Dh = 4.7 nm). Detailed studies indicated that the photoexcited NBD unit can generate singlet oxygen (1O2), which oxidizes the constituent phospholipids to transiently deteriorate the cell membrane. Reference membrane modifiers FLNBD-Oleyl and FLNBD-BAMPEG8k having shorter or longer hydrophilic spacers between the NBD and oleyl units showed a little or substantially no optoporation. For understanding these results, one must consider the following contradictory factors: (1) The photosensitized 1O2 generation efficiently occurs only when the NBD unit is in aqueous media, and (2) the lifetime of 1O2 in aqueous media is very short (3.0-3.5 µs). As supported experimentally and computationally, the hydrophilic spacer length of FLNBD-BAMPEG2k is optimal for compromising these factors. Further to note, the optoporation using FLNBD-BAMPEG2k is not accompanied by cytotoxicity.
Asunto(s)
Membrana Celular/metabolismo , Colorantes Fluorescentes/metabolismo , Oxadiazoles/metabolismo , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Membrana Celular/efectos de la radiación , Membrana Celular/ultraestructura , Permeabilidad de la Membrana Celular/efectos de los fármacos , Permeabilidad de la Membrana Celular/efectos de la radiación , Colorantes Fluorescentes/química , Humanos , Luz , Microscopía Confocal , Oxadiazoles/química , Fosfolípidos/metabolismo , Polietilenglicoles/química , Polietilenglicoles/metabolismo , Oxígeno Singlete/metabolismoRESUMEN
Molecular adhesion based on multivalent interactions plays essential roles in various biological processes. Hence, "molecular glues" that can adhere to biomolecules may modulate biomolecular functions and therefore can be applied to therapeutics. This tutorial review describes design strategies for developing adhesive motifs for biomolecules based on multivalent interactions. We highlight a guanidinium ion-based salt-bridge as a key interaction for adhesion to biomolecules and discuss the application of molecular glues for manipulation of biomolecular assemblies, drug delivery systems, and modulation of biomolecular functions.
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Carbohidratos/química , Guanidina/química , Ácidos Nucleicos/química , Péptidos/química , Estructura MolecularRESUMEN
We developed a water-soluble adhesive photoswitch (Gluen-Azo-SA, average n = 5) that selectively binds to a target enzyme and photochemically modulates its enzymatic activity even in cell lysates. Its design strategy features a photochromic azobenzene unit (Azo), which carries on one side an inhibitory motif for the target enzyme and on the other a glue part (Gluen) that utilizes its multiple guanidinium ion (Gu+) pendants for adhering onto the target surface. The target of Gluen-Azo-SA is carbonic anhydrase (CA) because sulfonamide (SA) derivatives, such as SA at the terminus of Gluen-Azo-SA, are known to bind selectively to the CA active site. The SA moiety, upon docking at the CA active site, possibly guides the connecting Gluen part to an oxyanion-rich area in proximity to the active site for adhesion, so that the conjugation between Gluen-Azo-SA and CA is ensured. With this geometry, the photochemical isomerization of the Azo unit likely generates a push-pull motion of SA, resulting in its docking and undocking at the active site of CA with the help of a competing substrate. Consequently, Gluen-Azo-SA can selectively photomodulate the enzymatic action of CA even in cell lysates. Azo-SA without Gluen can likewise suppress the enzymatic activity of CA by docking SA at its active site, but the resulting CA/Azo-SA conjugate, in contrast, does not respond to light.
Asunto(s)
Adhesivos/farmacología , Compuestos Azo/farmacología , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Guanidina/farmacología , Sulfonamidas/farmacología , Adhesivos/química , Compuestos Azo/química , Sitios de Unión/efectos de los fármacos , Inhibidores de Anhidrasa Carbónica/química , Guanidina/química , Estructura Molecular , Procesos Fotoquímicos , Solubilidad , Sulfonamidas/química , Propiedades de Superficie , Agua/químicaRESUMEN
Water-soluble linear polymers GumBAn (m/n = 18/6, 12/12, and 6/18) with multiple guanidinium ion (Gu(+)) and boronic acid (BA) pendants in their side chains were synthesized as ATP-responsive modulators for enzyme activity. GumBAn polymers strongly bind to the phosphate ion (PO4(-)) and 1,2-diol units of ATP via the Gu(+) and BA pendants, respectively. As only the Gu(+) pendants can be used for proteins, GumBAn is able to modulate the activity of enzymes in response to ATP. As a proof-of-concept study, we demonstrated that trypsin (Trp) can be deactivated by hybridization with GumBAn. However, upon addition of ATP, Trp was liberated to retrieve its hydrolytic activity due to a higher preference of GumBAn toward ATP than Trp. This event occurred in a much lower range of [ATP] than reported examples. Under cellular conditions, the hydrolytic activity of Trp was likewise modulated.
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Adenosina Trifosfato/química , Ácidos Borónicos/química , Tripsina/química , Espectrometría de FluorescenciaRESUMEN
With the world's focus on reducing our dependency on fossil-fuel energy, the scientific community can investigate new plastic materials that are much less dependent on petroleum than are conventional plastics. Given increasing environmental issues, the idea of replacing plastics with water-based gels, so-called hydrogels, seems reasonable. Here we report that water and clay (2-3 per cent by mass), when mixed with a very small proportion (<0.4 per cent by mass) of organic components, quickly form a transparent hydrogel. This material can be moulded into shape-persistent, free-standing objects owing to its exceptionally great mechanical strength, and rapidly and completely self-heals when damaged. Furthermore, it preserves biologically active proteins for catalysis. So far no other hydrogels, including conventional ones formed by mixing polymeric cations and anions or polysaccharides and borax, have been reported to possess all these features. Notably, this material is formed only by non-covalent forces resulting from the specific design of a telechelic dendritic macromolecule with multiple adhesive termini for binding to clay.
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Silicatos de Aluminio/química , Hidrogeles/química , Agua/análisis , Biocatálisis , Arcilla , Polímeros/químicaRESUMEN
PGlue(PZ), a pyrazoline (PZ)-based fluorescent adhesive which can be generated spatiotemporally in living systems, was developed. Since PGlue(PZ) carries many guanidinium ion (Gu(+)) pendants, it strongly adheres to various oxyanionic substrates through a multivalent salt-bridge interaction. PGlue(PZ) is given by bioorthogonal photopolymerization of a Gu(+)-appended monomer (Glue(TZ)), bearing tetrazole (TZ) and olefinic termini. Upon exposure to UV light, Glue(TZ) transforms into a nitrileimine (NI) intermediate (Glue(NI)), which is eligible for 1,3-dipolar polycycloaddition. However, Glue(NI) in aqueous media can concomitantly be deactivated into Glue(WA) by the addition of water, and the polymerization hardly occurs unless Glue(NI) is concentrated. We found that, even under high dilution, Glue(NI) is concentrated on oxyanionic substrates to a sufficient level for the polymerization, so that their surfaces can be point-specifically functionalized with PGlue(PZ) by the use of a focused beam of UV light.
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Adhesivos/química , Reacción de Cicloadición , Guanidina/química , Procesos Fotoquímicos , Polímeros/síntesis química , Pirazoles/química , Aniones/química , Ciclización , Estructura Molecular , Tamaño de la Partícula , Polímeros/química , Propiedades de SuperficieRESUMEN
A series of water-soluble telechelic dithiol monomers bearing multiple guanidinium ion (Gu(+)) units in their main chains were synthesized for packaging siRNA by template-assisted oxidative polymerization at their thiol termini. In the presence of siRNA, oxidative polymerization of (TEG)Gu4 affords a uniform-sized (7 ± 2 nm) nanocaplet containing siRNA (P(TEG)Gu4âsiRNA; P(TEG)Gu4 = polymerized (TEG)Gu4). When this small conjugate is incubated with live cells, cellular uptake occurs, and the nanocaplet undergoes depolymerization in the reductive cytosolic environment to liberate the packaged siRNA. Consequently, gene expression in the live cells is suppressed.
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Nanoestructuras , Polimerizacion , ARN Interferente Pequeño/administración & dosificación , Electroforesis en Gel de Agar , Microscopía Electrónica de Transmisión , Oxidación-ReducciónRESUMEN
A water-soluble dendron with a fluorescein isothiocyanate (FITC) fluorescent label and bearing nine pendant guanidinium ion (Gu(+))/benzophenone (BP) pairs at its periphery (Glue(BP)-FITC) serves as a "photoclickable molecular glue". By multivalent salt-bridge formation between Gu(+) ions and oxyanions, Glue(BP)-FITC temporarily adheres to a kinesin/microtubule hybrid. Upon subsequent exposure to UV light, this noncovalent binding is made permanent via a cross-linking reaction mediated by carbon radicals derived from the photoexcited BP units. This temporal-to-permanent transformation by light occurs quickly and efficiently in this preorganized state, allowing the movements of microtubules on a kinesin-coated glass plate to be photochemically controlled. A fundamental difference between such temporal and permanent bindings was visualized by the use of "optical tweezers".
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Benzofenonas/química , Fluoresceína-5-Isotiocianato/química , Colorantes Fluorescentes/química , Guanidina/química , Cinesinas/química , Microtúbulos/química , Animales , Cationes Monovalentes/química , Bovinos , Cinesinas/ultraestructura , Microtúbulos/ultraestructura , Modelos Moleculares , Procesos Fotoquímicos , Albúmina Sérica Bovina/química , Rayos UltravioletaRESUMEN
A water-soluble photoresponsive molecular glue, Azo-(18)Glue, consisting of a photochromic azobenzene core and two adhesive dendritic wedges with a total of 18 peripheral guanidinium ion (Gu(+)) pendants tightly adheres to the surface of a phospholipid membrane, even in buffer, via a multivalent salt-bridge formation with phosphate anions. A photomechanical motion of adhering Azo-(18)Glue possibly gives rise to dynamic structural disordering of the phospholipid membrane and activates transmembrane ion permeation. In sharp contrast, no activation of ion permeation results when poorly adhesive Azo-(6)Glue carrying only six Gu(+) pendants is used in place of Azo-(18)Glue.
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Fricción , Fosfolípidos/química , Procesos Fotoquímicos , Iones , PermeabilidadRESUMEN
Nanocapsules that collapse in response to guanosine triphosphate (GTP) have the potential as drug carriers for efficiently curing diseases caused by cancer and RNA viruses because GTP is present at high levels in such diseased cells and tissues. However, known GTP-responsive carriers also respond to adenosine triphosphate (ATP), which is abundant in normal cells as well. Here, we report the elaborate reconstitution of microtubule into a nanocapsule that selectively responds to GTP. When the tubulin monomer from microtubule is incubated at 37 °C with a mixture of GTP (17 mol%) and nonhydrolysable GTP* (83 mol%), a tubulin nanosheet forms. Upon addition of photoreactive molecular glue to the resulting dispersion, the nanosheet is transformed into a nanocapsule. Cell death results when a doxorubicin-containing nanocapsule, after photochemically crosslinked for properly stabilizing its shell, is taken up into cancer cells that overexpress GTP.
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Nanocápsulas , Tubulina (Proteína) , Adenosina Trifosfato/metabolismo , Doxorrubicina/metabolismo , Doxorrubicina/farmacología , Guanosina Trifosfato/metabolismo , Microtúbulos/metabolismo , Tubulina (Proteína)/metabolismoRESUMEN
Dendron G1(Gu(+))(9)R and linear peptide oligomer Asn(TEG-Gu(+))(9), decorated with multiple guanidinium (Gu(+)) ions as sticky pendants via an oligo(oxyethylene) spacer, adhere to BSA and protein assemblies such as microtubules in aqueous buffers. Using fluorescently labeled G1(Gu(+))(9)R with pyrenyl and rhodamine focal cores, the adhesion process can be visualized by FRET or confocal laser scanning microscopy. The adhesion to microtubules leads to their stabilization against depolymerization into alpha/beta-tubulin heterodimer components, where the effects of G1(Gu(+))(9)R and Asn(TEG-Gu(+))(9) are comparable to that of paclitaxel, known as an anticancer drug. Since G1(Gu(+))(9)R and Asn(TEG-Gu(+))(9) are superior to lower-generation G0(Gu(+))(3)OMe and arginine nonamer, respectively, the multivalency of the interaction and a conformational flexibility of the oligoether spacers play a crucial role in the efficient adhesion to proteins.
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Dendrímeros/química , Guanidina/química , Microtúbulos/química , Oligopéptidos/química , Modelos Moleculares , Albúmina Sérica Bovina/químicaRESUMEN
The cell nucleus is one of the most important organelles as a subcellular drug-delivery target, since modulation of gene replication and expression is effective for treating various diseases. Here, we demonstrate light-triggered nuclear translocation of guests using caged molecular glue (CagedGlue-R) tags, whose multiple guanidinium ion (Gu+) pendants are protected by an anionic photocleavable group (butyrate-substituted nitroveratryloxycarbonyl; BANVOC). Guests tagged with CagedGlue-R are taken up into living cells via endocytosis and remain in endosomes. However, upon photoirradiation, CagedGlue-R is converted into uncaged molecular glue (UncagedGlue-R) carrying multiple Gu+ pendants, which facilitates the endosomal escape and subsequent nuclear translocation of the guests. This method is promising for site-selective nuclear-targeting drug delivery, since the tagged guests can migrate into the cytoplasm followed by the cell nucleus only when photoirradiated. CagedGlue-R tags can deliver macromolecular guests such as quantum dots (QDs) as well as small-molecule guests. CagedGlue-R tags can be uncaged with not only UV light but also two-photon near-infrared (NIR) light, which can deeply penetrate into tissue.