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1.
Chemistry ; 26(2): 534-542, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31638287

RESUMO

The interlocking of ring and axle molecular components in rotaxanes provides a way to combine chromophoric, electron-donor and electron-acceptor moieties in the same molecular entity, in order to reproduce the features of photosynthetic reaction centers. To this aim, the photoinduced electron transfer processes involving a 1,8-naphthalimide chromophore, embedded in several rotaxane-based dyads, were investigated by steady-state and time-resolved absorption and luminescence spectroscopic experiments in the 300 fs-10 ns time window. Different rotaxanes built around the dialkylammonium/ dibenzo[24]crown-8 ether supramolecular motif were designed and synthesized to decipher the relevance of key structural factors, such as the chemical deactivation of the ammonium-crown ether recognition, the presence of a secondary site for the ring along the axle, and the covalent functionalization of the macrocycle with a phenothiazine electron donor. Indeed, the conformational freedom of these compounds gives rise to a rich dynamic behavior induced by light and may provide opportunities for investigating and understanding phenomena that take place in complex (bio)molecular architectures.


Assuntos
Naftalimidas/química , Rotaxanos/química , Éteres de Coroa/química , Transporte de Elétrons , Luz , Fenotiazinas/química , Teoria Quântica , Rotaxanos/síntese química , Espectrometria de Fluorescência
2.
Analyst ; 144(21): 6415-6421, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31580336

RESUMO

In this study, an electroactive rotaxane, (S,S)-crown-3, consisting of a polymeric chiral ionic liquid as a flexible axle and 18-crown-6 as the wheel, was designed and synthesized. It is worth noting that a stimuli-responsive system was developed, in which the wheel could switch its location between the chiral carbamido group and ionic pair of the ionic polymers under an external force. Next, (S,S)-crown-3 was employed as a modification on the surface of glassy electrode. In contrast to previous study, the developed probe presented a clear discrimination of an electrochemical signal in the absence of Cu(ii). Under the external force (different pH values), l-isomers of amino acids (tryptophan, tyrosine, and cysteine) could form stable host-guest interactions with the chiral carbamido group, producing higher peak currents than the d-isomers. Compared to the absence of the crown, (S,S)-crown-3 showed much better recognition efficiency. The value of IL/ID for tryptophan could reach 39.8. In brief, the present study describes a powerful method for the synthesis of an electroactive rotaxane with great enantiorecognition capability.


Assuntos
Aminoácidos/química , Rotaxanos/química , Rotaxanos/síntese química , Técnicas de Química Sintética , Eletroquímica , Análise Espectral , Estereoisomerismo
3.
Nat Protoc ; 14(10): 2818-2855, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31511665

RESUMO

Mechanically interlocked DNA nanostructures are useful as flexible entities for operating DNA-based nanomachines. Interlocked structures made of double-stranded (ds) DNA components can be constructed by irreversibly threading them through one another to mechanically link them. The interlocked components thus remain bound to one another while still permitting large-amplitude motion about the mechanical bond. The construction of interlocked dsDNA architectures is challenging because it usually involves the synthesis and modification of small dsDNA nanocircles of various sizes, dependent on intrinsically curved DNA. Here we describe the design, generation, purification, and characterization of interlocked dsDNA structures such as catenanes, rotaxanes, and daisy-chain rotaxanes (DCRs). Their construction requires precise control of threading and hybridization of the interlocking components at each step during the assembly process. The protocol details the characterization of these nanostructures with gel electrophoresis and atomic force microscopy (AFM), including acquisition of high-resolution AFM images obtained in intermittent contact mode in liquid. Additional functionality can be conferred on the DNA architectures by incorporating proteins, molecular switches such as photo-switchable azobenzene derivatives, or fluorophores for studying their mechanical behavior by fluorescence quenching or fluorescent resonance energy transfer experiments. These modified interlocked DNA architectures provide access to more complex mechanical devices and nanomachines that can perform a variety of desired functions and operations. The assembly of catenanes can be completed in 2 d, and that of rotaxanes in 3 d. Addition of azobenzene functionality, fluorophores, anchor groups, or the site-specific linkage of proteins to the nanostructure can extend the time line.


Assuntos
Catenanos/química , DNA/química , Nanoestruturas/química , Nanotecnologia/métodos , Hibridização de Ácido Nucleico/métodos , Rotaxanos/química , DNA/síntese química , Luz , Microscopia de Força Atômica
4.
Macromol Rapid Commun ; 40(20): e1900323, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31429992

RESUMO

Reversible covalent bonds yield polymeric materials with functional characteristics such as self-healing, shape memory, stress relaxation, and stimuli-responsiveness. Here, photo-reversibly cappable polyrotaxanes are designed and the on-off controlled dissociation of their supramolecular architectures is demonstrated. The polyrotaxanes are synthesized by capping dithiobenzoates at both terminals of polyethylene glycol threaded through multiple α-cyclodextrins. Since dethreading of the α-cyclodextrins is prevented by the dithiobenzoate stoppers, the supramolecular dissociation is induced by their photo-cleavage. Subsequently, the cleaved dithiobenzoates spontaneously re-cap the polyrotaxane terminals in darkness. Thus, the supramolecular dissociation can be modulated by photo-reversible capping of the dithiobenzoate stoppers. These polyrotaxanes with dithiobenzoate stoppers are promising functional materials for photo-controlling physical properties and structures.


Assuntos
Ciclodextrinas/química , Luz , Poloxâmero/química , Rotaxanos/química , Benzoatos/química , Ciclodextrinas/síntese química , Poloxâmero/síntese química , Polietilenoglicóis/química , Rotaxanos/síntese química , alfa-Ciclodextrinas/química
5.
Molecules ; 24(15)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31344932

RESUMO

Two types of mono-ester-functionalized pillar[5]arenes, P1 and P2, bearing different side-chain groups, were synthesized. Their host-guest complexation and self-inclusion properties were studied by 1H NMR and 2D nuclear overhauser effect spectroscopy (NOESY) NMR measurements. The results showed that the substituents on their phenolic units have a great influence on the self-assembly of both pillar[5]arenes, although they both could form stable pseudo[1]rotaxanes at room temperature. When eight bulky 4-brombutyloxy groups were capped on the cavity, instead of methoxy groups, pseudo[1]rotaxane P1 became less stable and its locked ester group in the inner space of cavity was not as deep as P2, leading to distinctly different host-guest properties between P1 and P2 with 1,6-dibromohexane. Moreover, pillar[5]arene P1 displayed effective molecular recognition toward 1,6-dichlorohexane and 1,2-bromoethane among the guest dihalides. In addition, the self-complex models and stabilities between P1 and P2 were also studied by computational modeling and experimental calculations.


Assuntos
Calixarenos/química , Modelos Químicos , Rotaxanos/química , Ésteres , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Eletricidade Estática
6.
Chem Commun (Camb) ; 55(50): 7203-7206, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31165120

RESUMO

Failure of autophagy induction results in the accumulation of abnormal mitochondria to cause neurodegenerative diseases. Artificial autophagy activation via the mitochondrial delivery of polyrotaxane with autophagy induced activity is achieved using a MITO-Porter, a nanodevice for mitochondrial delivery. This strategy can be applied to innovative research and therapy.


Assuntos
Autofagia/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Nanotecnologia/instrumentação , Rotaxanos/química , beta-Ciclodextrinas/farmacologia , Células HeLa , Humanos , Metilação , beta-Ciclodextrinas/química
7.
Mater Sci Eng C Mater Biol Appl ; 99: 159-170, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30889688

RESUMO

A magnetic-pH dual responsive drug delivery system was prepared for antibacterial therapy to reduce the side effects on nonpathological cells or tissues. Iron oxide (Fe3O4) core was surface-functionalized with silane coupling agents to link ß­cyclodextrin (ß-CD) (CDMNP), and a polypseudorotaxanes shell where polyethyleneglycol chains threaded much CD molecules was further prepared on the magnetic Fe3O4 core (CDMNP-PEG-CD) to enhance loading capacity of roxithromycin (ROX). CDMNP-PEG-CD with a hydrodynamic diameter of ~168 nm was cytocompatible, superparamagnetic, magnetic-responsive and stable for 180 min of storage. No significant interaction with serum albumin was shown for the nanocomposites. The in vitro release from ROX-loaded CDMNP-PEG-CD nanocomposites was about 76% of total drug within 30 min at pH 1.0, 1.6-fold of that at pH 7.4 and 2-fold of that at pH 8.0, presenting pH-responsive drug release behaviors. The nanocomposites showed positive antibacterial activity against both E. coli and S. aureus based on an agar diffusion method. The antibacterial activity of the nanocomposites was more sensitive against E. coli than S. aureus, and the inhibition halo against E. coli was 85% more than that of Fe3O4. CDMNP-PEG-CD nanocomposites allowed for the localization and fast concentration of hydrophobic drugs, providing a broad potential range of therapeutic applications.


Assuntos
Ciclodextrinas/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Nanopartículas de Magnetita/química , Poloxâmero/química , Rotaxanos/química , Roxitromicina/farmacologia , Adsorção , Antibacterianos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Escherichia coli/efeitos dos fármacos , Humanos , Nanopartículas de Magnetita/ultraestrutura , Testes de Sensibilidade Microbiana , Nanocompostos/química , Nanocompostos/ultraestrutura , Tamanho da Partícula , Polietilenoglicóis/química , Soroalbumina Bovina/química , Dióxido de Silício/química , Espectroscopia de Infravermelho com Transformada de Fourier , Staphylococcus aureus/efeitos dos fármacos , Termogravimetria , Difração de Raios X , beta-Ciclodextrinas/química
8.
Chem Commun (Camb) ; 55(21): 3156-3159, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30801096

RESUMO

Room temperature phosphorescent (RTP) γ-CD-CB[6]-cowheeled [4]rotaxanes were synthesized by implanting a naphthalene axle into the cavity of iodine-substituted γ-CDs. The strong green RTP was quenched exclusively by Trp while no RTP quenching was observed with other major physiological amino acids or with the Trp-containing protein HSA, demonstrating a highly specific sensing of free Trp.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Imidazóis/química , Substâncias Luminescentes/química , Rotaxanos/química , Triptofano/análise , gama-Ciclodextrinas/química , Hidrocarbonetos Aromáticos com Pontes/síntese química , Humanos , Imidazóis/síntese química , Substâncias Luminescentes/síntese química , Medições Luminescentes/métodos , Rotaxanos/síntese química , Temperatura Ambiente , Triptofano/sangue , gama-Ciclodextrinas/síntese química
9.
Yakugaku Zasshi ; 139(2): 143-155, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30713223

RESUMO

Recently, the application of ß-cyclodextrins (ß-CDs) as therapeutic agents has received considerable attention. ß-CDs have been reported to have therapeutic effects on various diseases, such as Niemann-Pick type C (NPC) disease, a family of lysosomal storage disorders characterized by the lysosomal accumulation of cholesterol. To further improve the therapeutic efficacy of ß-CDs, the use of ß-CD-threaded polyrotaxanes (PRXs) has been proposed as a carrier of ß-CDs for NPC disease. PRXs are supramolecular polymers composed of many CDs threaded onto a linear polymer chain and capped with bulky stopper molecules. In this review, the design of PRXs and their therapeutic applications are described. To achieve the intracellular release of threaded ß-CDs from PRXs, stimuli-cleavable linkers are introduced in an axle polymer of PRXs. The stimuli-labile PRXs can dissociate into their constituent molecules by a cleavage reaction under specific stimuli, such as pH reduction in lysosomes. The release of the threaded ß-CDs from acid-labile PRXs in acidic lysosomes leads to the formation of an inclusion complex with the cholesterol that has accumulated in NPC disease patient-derived fibroblasts, thus promoting the extracellular excretion of the excess cholesterol. Moreover, the administration of PRXs to a mouse model of NPC disease caused significant suppression of the tissue accumulation of cholesterol, resulting in a prolonged life span in the model mice. Additionally, the induction of autophagy by the methylated ß-CD-threaded PRXs (Me-PRXs) is described. Accordingly, the stimuli-labile PRXs are expected to be effective carriers of CDs for therapeutic applications.


Assuntos
Ciclodextrinas , Portadores de Fármacos , Poloxâmero , Rotaxanos , beta-Ciclodextrinas/administração & dosagem , Animais , Autofagia/efeitos dos fármacos , Colesterol/metabolismo , Ciclodextrinas/química , Ciclodextrinas/metabolismo , Modelos Animais de Doenças , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Desenho de Drogas , Fibroblastos/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Lisossomos/metabolismo , Substâncias Macromoleculares , Metilação , Camundongos , Doenças de Niemann-Pick/tratamento farmacológico , Doenças de Niemann-Pick/metabolismo , Poloxâmero/química , Poloxâmero/metabolismo , Rotaxanos/química , Rotaxanos/metabolismo , beta-Ciclodextrinas/metabolismo , beta-Ciclodextrinas/farmacologia
10.
Yakugaku Zasshi ; 139(2): 175-183, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30713226

RESUMO

Supramolecular chemistry is a useful and important domain for understanding pharmaceutical sciences, since various physiological reactions (e.g., protein association) and drug activities (e.g., the substrate/receptor reaction) are based on supramolecular chemistry. Biological components, such as DNA and cells, are also supermolecules. However, supramolecular chemistry to date has not been a major domain in the field of pharmaceutical study. In this article, we propose a new concept in pharmaceutical sciences termed "supramolecular pharmaceutical sciences" which combines pharmaceutical sciences and supramolecular chemistry. "Supramolecular pharmaceutical sciences" could encompass strictly controlled molecular arrangement, stimulus responsible molecular motion, new functions beyond those of existing molecules, more accurate drug design, new active pharmaceutical ingredients, new perspectives for the investigation of the drug mechanisms, and novel pharmaceutical technologies. Moreover, pharmaceutical sciences are useful for supramolecular chemistry, because biological reactions are very accurate reactions, making this a win-win relationship. Thus, supramolecular pharmaceutical sciences could be useful for developing new methods, hypotheses, ideas, materials, mechanisms, and strategies in the realm of pharmaceutical science.


Assuntos
Biofarmácia/tendências , Desenho de Drogas , Previsões , Substâncias Macromoleculares/química , Antracenos/química , Ciclodextrinas/química , Hidrogéis , Conformação Molecular , Poloxâmero/química , Polietilenoglicóis , Rotaxanos/química , Tecnologia Farmacêutica/tendências
11.
Molecules ; 24(3)2019 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-30691115

RESUMO

Macrophages play an important role in the regulation of inflammation and immune response as well as the pathogenesis of chronic inflammatory diseases and cancer. Therefore, targeted delivery of therapeutic reagents to macrophages is an effective method for treatment and diagnosis. We previously examined the therapeutic applications of polyrotaxanes (PRXs) comprised of multiple cyclodextrins (CDs) threaded on a polymer chain and capped with bulky stopper molecules. In the present study, we designed an α-d-mannose-modified α-CD/poly(ethylene glycol)-based PRX (Man-PRX). The intracellular uptake of Man-PRX through the interaction with macrophage mannose receptor (MMR) in macrophage-like RAW264.7 cells was examined. Intracellular Man-PRX uptake was observed in MMR-positive RAW264.7 cells but was negligible in MMR-negative NIH/3T3 cells. In addition, the intracellular Man-PRX uptake in RAW264.7 cells was significantly inhibited in the presence of free α-d-mannose and an anti-MMR antibody, which suggests that MMR is involved in the intracellular uptake of Man-PRX. Moreover, the polarization of RAW264.7 cells affected the Man-PRX internalization efficiency. These results indicate that Man-PRX is an effective candidate for selective targeting of macrophages through a specific interaction with the MMR.


Assuntos
Endocitose/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Manose/química , Receptores de Superfície Celular/metabolismo , Rotaxanos/química , Rotaxanos/farmacologia , Animais , Polaridade Celular/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Camundongos , Células NIH 3T3 , Células RAW 264.7 , Rotaxanos/síntese química
12.
Macromol Biosci ; 19(4): e1800346, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30624848

RESUMO

Modulation of material properties and growth factor application are critical in constructing suitable cell culture environments to induce desired cellular functions. Sulfonated polyrotaxane (PRX) surfaces with immobilized vascular endothelial growth factors (VEGFs) are prepared to improve network formation in vascular endothelial cells. Sulfonated PRXs, whereby sulfonated α-cyclodextrins (α-CDs) are threaded onto a linear poly(ethylene glycol) chain capped with bulky groups at both terminals, are coated onto surfaces. The molecular mobility of sulfonated PRX surfaces is modulated by tuning the number of threading α-CDs. VEGF is immobilized onto surfaces with varying mobility. Low mobility and VEGF-immobilization reinforce cell proliferation, yes-associated protein activity, and rhoA, pdgf, ang-1, and pecam-1 gene expression. Highly mobile surfaces and soluble VEGF weakly affect these cell responses. Network formation is strongly stimulated in vascular endothelial cells only on low-mobility VEGF-immobilized surfaces, suggesting that molecular mobility and VEGF immobilization synergistically control cell function.


Assuntos
Materiais Biocompatíveis/química , Ciclodextrinas/química , Células Endoteliais da Veia Umbilical Humana/metabolismo , Proteínas Imobilizadas , Microvasos/crescimento & desenvolvimento , Poloxâmero/química , Rotaxanos/química , Fator A de Crescimento do Endotélio Vascular , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Proteínas Imobilizadas/química , Proteínas Imobilizadas/farmacologia , Polietilenoglicóis/química , Propriedades de Superfície , Fator A de Crescimento do Endotélio Vascular/química , Fator A de Crescimento do Endotélio Vascular/farmacologia , alfa-Ciclodextrinas/química
13.
Macromol Biosci ; 19(4): e1800478, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30694599

RESUMO

The use of natural compounds to construct biomaterials, including delivery system, is an attractive strategy. In the present study, through threading functional α-cyclodextrins onto the conjugated macromolecules of poly(ethylene glycol) (PEG) and natural compound bile acid, glycopolymers of polyrotaxanes with the active targeting ability are obtained. These glycopolymers self-assemble into micelles as evidenced by dynamic light scattering and transmission electron microscopy, in which glucosamine, as an example of targeting groups, is introduced. These micelles after loading doxorubicin (DOX) exhibit the selective recognition with cancer cells 4T1. Meanwhile, the maximal half inhibitory concentration is determined to be ≈2.5 mg L-1 for the DOX-loaded micelles, close to the value of free DOX·HCl (1.9 mg L-1 ). The cumulative release of DOX at pH 5.5 is faster than at pH 7.4, which may be used as the controlled release system. This drug delivery system assembled by glycopolymers features high drug loading of DOX, superior biocompatibility. The strategy not only utilizes the micellization induced by bile acids, but also overcomes the major limitation of PEG such as the lack of targeting groups. In particular, this drug delivery platform can extend to grafting the other targeting groups, rendering this system more versatile.


Assuntos
Ácidos e Sais Biliares , Doxorrubicina , Portadores de Fármacos , Micelas , Neoplasias Experimentais/tratamento farmacológico , Rotaxanos , Animais , Ácidos e Sais Biliares/química , Ácidos e Sais Biliares/farmacocinética , Ácidos e Sais Biliares/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Camundongos , Células NIH 3T3 , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Coelhos , Rotaxanos/química , Rotaxanos/farmacocinética , Rotaxanos/farmacologia
14.
Colloids Surf B Biointerfaces ; 176: 276-287, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30623815

RESUMO

Self-assembled polypseudorotaxanes (PPRXs) fabricated with α-cyclodextrin and poly(ethylene glycol) (PEG) or its thiolated derivatives were candidate functional materials for enzyme soft-immobilization, encapsulation and controlled-release. The study of their interaction with Jack bean urease (JBU) indicated that they inconspicuously influenced the activity and stability of JBU during long storage, up to 30 days. The macro-species were inaccessible to JBU's active site and the steric effect might play a significant role in the stabilization of JBU, when compared with the small-molecular sulfhydryl inhibitor thioglycolic acid. Circular dichroism and fluorescence spectra analyses revealed that thiolated PEG400-(SH)2 and its assembly PPRX400(SH) brought in perturbations to certain α-helical or ß-sheet domains of JBU, making JBU's conformation more flexible. The resulting partial unfolding of domains exposed several hydrophobic clusters and varied JBU's surface hydrophobicity. It also rendered the chromophores more hydrophilic and more bared to the polar environment, leading to the typical bathochromic-shift and quenching in intrinsic and synchronous fluorescence spectra. Moreover, the surface hydrophobicity profile of JBU was depicted by fluorescent probe monitoring and the unique "hydrophobic cave" motif was proposed by analyzing JBU's structural data from the Protein Data Bank. It should be pointed out that conformational variations mainly occurred at the surface region of JBU, while the buried active bi-nickel center was not markedly influenced by the macro-species. The results demonstrated that the PPRXs might act as a proper carrier for JBU encapsulation or soft-immobilization.


Assuntos
Canavalia/enzimologia , Ciclodextrinas/química , Poloxâmero/química , Polietilenoglicóis/química , Rotaxanos/química , Compostos de Sulfidrila/química , Urease/metabolismo , alfa-Ciclodextrinas/química , Dicroísmo Circular , Estabilidade Enzimática , Interações Hidrofóbicas e Hidrofílicas , Cinética , Espectrometria de Fluorescência
15.
Colloids Surf B Biointerfaces ; 173: 85-93, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30273872

RESUMO

Encapsulation techniques to generate core/shell systems provide a method that improves physicochemical properties, which are very important in biological applications. ß-carotene is a common carotenoid that has shown preventive effects in skin diseases and vitamin A deficiency but this compound has limited water solubility and bioavailability, which hinder its broad application. The use of polyrotaxane compounds formed from cyclodextrins has allowed supramolecular polymer micelles (SMPMs) to be synthesized to encapsulate ß-carotene. The polymeric compound Pluronic F127® was also used to create core/shell nanoparticles (NPs) that contain ß-carotene. Bioactive compound encapsulation was fully confirmed by nuclear magnetic resonance spectroscopy and by scanning and transmission electron microscopy. The method based on cyclodextrin and lecithin allow to release slowly when the systems were exposed to an aqueous medium by pH control, with an increase of 16 times of bioavailability comparing with free carotenoid. This allowed to potentiate the cytotoxic activity on a melanoma cell line by enhancing the water solubility to more than 28 mg/L, and present promising applications of SMPMs to provitamins.


Assuntos
Antioxidantes/química , Citotoxinas/química , Preparações de Ação Retardada , Composição de Medicamentos/métodos , Nanopartículas/química , beta Caroteno/química , Antioxidantes/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclodextrinas/química , Citotoxinas/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Lecitinas/química , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Micelas , Nanopartículas/ultraestrutura , Poloxâmero/química , Rotaxanos/química , Solubilidade , beta Caroteno/farmacologia
16.
J Am Chem Soc ; 140(51): 17992-17998, 2018 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-30445811

RESUMO

Inspired by natural biomolecular machines, synthetic molecular-level machines have been proven to perform well-defined mechanical tasks and measurable work. To mimic the function of channel proteins, we herein report the development of a synthetic molecular shuttle, [2]rotaxane 3, as a unimolecular vehicle that can be inserted into lipid bilayers to perform passive ion transport through its stochastic shuttling motion. The [2]rotaxane molecular shuttle is composed of an amphiphilic molecular thread with three binding stations, which is interlocked in a macrocycle wheel component that tethers a K+ carrier. The structural characteristics enable the rotaxane to transport ions across the lipid bilayers, similar to a cable car, transporting K+ with an EC50 value of 1.0 µM (3.0 mol % relative to lipid). We expect that this simple molecular machine will provide new opportunities for developing more effective and selective ion transporters.


Assuntos
Transporte de Íons , Bicamadas Lipídicas/metabolismo , Potássio/metabolismo , Rotaxanos/metabolismo , Concentração de Íons de Hidrogênio , Modelos Químicos , Rotaxanos/síntese química , Rotaxanos/química
17.
Biomater Sci ; 6(12): 3126-3138, 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30362476

RESUMO

As a supramolecular macrocyclic polymer, cyclodextrin (CD) polyrotaxanes (PRs) have many advantages for developing nanomedicines, such as stable chemical composition, abundant functionalized hydroxyl groups, moving across biological barriers, adjustable nanoparticle size and good biocompatibility. Herein, we synthesized a class of acid-active therapeutic nanoparticles comprising a α-CD-based PR polymeric prodrug of PRs-poly(doxorubicin)-co-poly[(ethylene glycol) methyl ether methacrylate] (PR-PDOX-co-POEGMA, denoted as PRMO@DOX) to reduce drug leakage and selectively deliver drugs into tumor cells, aiming to achieve maximal treatment efficacy of supramolecular therapeutics. The obtained PRMO@DOX showed desirable features of high drug loading rates (>25 wt%), fast cellular uptake, acid-active controlled release, effective anti-tumor activity and low systemic toxicity. Benefiting from its unique amphiphilic nanostructure, PRMO@DOX can form water-soluble prodrug nanoparticles in aqueous media. The acid-active hydrazone bond in the prodrug can break and thus release drug molecules precisely and in a timely manner under an acidic tumor microenvironment, damaging the nuclei and mitochondria of tumor cells. Both in vitro and in vivo experiments clearly demonstrated a remarkable antitumor efficacy of this therapeutic platform, which provided a new strategy for the development of polyrotaxane-based nanomedicine for enhanced cancer therapy.


Assuntos
Núcleo Celular/efeitos dos fármacos , Ciclodextrinas/química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Nanopartículas/química , Rotaxanos/química , Ácidos/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ciclodextrinas/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Células HeLa , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Nanopartículas/efeitos adversos , Rotaxanos/efeitos adversos , Microambiente Tumoral
18.
Nucleic Acids Res ; 46(17): 8710-8719, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30260454

RESUMO

Interlocked structures, such as rotaxane and catenane, combine both static and dynamic properties. To expand their unique properties into the chemical biology field, a spontaneous formation method of the interlocked structures with the target would be ideal. We have previously developed a pseudorotaxane-forming oligo DNA (prfODN) to spontaneously form topological DNA/RNA architectures. In this study, we report the structural optimization of prfODNs for the efficient and stable complex formation. The optimized prfODNs efficiently formed pseudorotaxane structures with a DNA or RNA target, and the yield for the RNA target reached 85% in 5 min. In addition, the optimized prfODNs could form the pseudorotaxane structure with a smaller ring size and the structure significantly increased the kinetic stability. Furthermore, the catenane structure was successfully formed with the optimized prfODNs to provide the conclusive evidence for the formation of the threaded structure. This information will be valuable for developing new chemical methods using functional nucleic acids for antisense oligo nucleotides and DNA/RNA nanotechnology.


Assuntos
Antracenos/química , DNA/química , Oligonucleotídeos/química , RNA/química , Rotaxanos/química , DNA/genética , Simulação de Acoplamento Molecular , Estrutura Molecular , Conformação de Ácido Nucleico , Oligonucleotídeos/genética , RNA/genética , Termodinâmica
19.
Carbohydr Polym ; 200: 278-288, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30177168

RESUMO

This work aimed to design supramolecular gels combining Soluplus or Solutol and alfa- and hydroxypropyl-ß-cyclodextrin (α-CD, HPß-CD) for carvedilol (CAR) transdermal delivery. Poly(pseudo)rotaxane formation (appearance, SEM, 1H NMR), drug solubilization, rheological properties and in vitro release were investigated. CAR-CD complexes were prepared in situ or by spray drying. For Solutol, poly(pseudo)rotaxanes were formed immediately after mixing with α-CD and did not influence CAR solubility. Differently, Soluplus poly(pseudo)rotaxanes took 24-48 h to be formed and CAR solubility decreased compared to Soluplus micelles. Soluplus 20% + α-CD (5-10%) showed higher G' and G'' but also faster CAR release than Solutol poly(pseudo)rotaxanes, which is explained by the different location of PEG chains in the two amphiphilic polymers. Faster drug release was achieved incorporating HPß-CD or CAR-HPß-CD spray-dried complexes. The results evidenced the versatility of the formulations in terms of rheological behavior and drug release patterns, which can be adjusted for CAR transdermal delivery.


Assuntos
Carbazóis/química , Carbazóis/metabolismo , Ciclodextrinas/química , Portadores de Fármacos/química , Poloxâmero/química , Propanolaminas/química , Propanolaminas/metabolismo , Rotaxanos/química , Pele/metabolismo , Carvedilol , Liberação Controlada de Fármacos , Reologia , Solubilidade
20.
Chem Commun (Camb) ; 54(62): 8645-8648, 2018 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-30022209

RESUMO

As an extension of actinide-rotaxane complexes from uranium to transuranium, we report the first crystal structure of a neptunium-rotaxane complex, NRCP-1, in which an interwoven neptunium(v)-rotaxane coordination network incorporating a mechanically-interlocked [c2]daisy chain unit is promoted via the simultaneous coordination of cucurbituril (CB6) and axle molecules in [2]pseudorotaxane to NpV.


Assuntos
Complexos de Coordenação/química , Netúnio/química , Rotaxanos/química , Urânio/química , Elementos da Série Actinoide/química , Complexos de Coordenação/síntese química , Modelos Moleculares , Conformação Molecular
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