RESUMO
Mitochondrial DNA (mtDNA) is known to play a critical role in cellular functions. However, the fluorescent probe enantio-selectively targeting live-cell mtDNA is rare. We recently found that the well-known DNA 'light-switch' [Ru(phen)2dppz]Cl2 can image nuclear DNA in live-cells with chlorophenolic counter-anions via forming lipophilic ion-pairing complex. Interestingly, after washing with fresh-medium, [Ru(phen)2dppz]Cl2 was found to re-localize from nucleus to mitochondria via ABC transporter proteins. Intriguingly, the two enantiomers of [Ru(phen)2dppz]Cl2 were found to bind enantio-selectively with mtDNA in live-cells not only by super-resolution optical microscopy techniques (SIM, STED), but also by biochemical methods (mitochondrial membrane staining with Tomo20-dronpa). Using [Ru(phen)2dppz]Cl2 as the new mtDNA probe, we further found that each mitochondrion containing 1-8 mtDNA molecules are distributed throughout the entire mitochondrial matrix, and there are more nucleoids near nucleus. More interestingly, we found enantio-selective apoptotic cell death was induced by the two enantiomers by prolonged visible light irradiation, and in-situ self-monitoring apoptosis process can be achieved by using the unique 'photo-triggered nuclear translocation' property of the Ru complex. This is the first report on enantio-selective targeting and super-resolution imaging of live-cell mtDNA by a chiral Ru complex via formation and dissociation of ion-pairing complex with suitable counter-anions.
Assuntos
DNA Mitocondrial , Microscopia , Rutênio , Ânions , Luz , Mitocôndrias , Rutênio/química , Microscopia/métodosRESUMO
Oral treatment of colon diseases with the CRISPR/Cas9 system has been hampered by the lack of a safe and efficient delivery platform. Overexpressed CD98 plays a crucial role in the progression of ulcerative colitis (UC) and colitis-associated colorectal cancer (CAC). In this study, lipid nanoparticles (LNPs) derived from mulberry leaves are functionalized with Pluronic copolymers and optimized to deliver the CRISPR/Cas gene editing machinery for CD98 knockdown. The obtained LNPs possessed a hydrodynamic diameter of 267.2 nm, a narrow size distribution, and a negative surface charge (-25.6 mV). Incorporating Pluronic F127 into LNPs improved their stability in the gastrointestinal tract and facilitated their penetration through the colonic mucus barrier. The galactose end groups promoted endocytosis of the LNPs by macrophages via asialoglycoprotein receptor-mediated endocytosis, with a transfection efficiency of 2.2-fold higher than Lipofectamine 6000. The LNPs significantly decreased CD98 expression, down-regulated pro-inflammatory cytokines (TNF-α and IL-6), up-regulated anti-inflammatory factors (IL-10), and polarized macrophages to M2 phenotype. Oral administration of LNPs mitigated UC and CAC by alleviating inflammation, restoring the colonic barrier, and modulating intestinal microbiota. As the first oral CRISPR/Cas9 delivery LNP, this system offers a precise and efficient platform for the oral treatment of colon diseases.
Assuntos
Sistemas CRISPR-Cas , Lipídeos , Morus , Nanopartículas , Folhas de Planta , Nanopartículas/química , Folhas de Planta/química , Animais , Administração Oral , Morus/química , Lipídeos/química , Camundongos , Doenças do Colo/terapia , Humanos , Masculino , LipossomosRESUMO
Bone homeostasis is maintained by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. A dramatic decrease in estrogen levels in postmenopausal women leads to osteoclast overactivation, impaired bone homeostasis, and subsequent bone loss. Changes in the gut microbiome affect bone mineral density. However, the role of the gut microbiome in estrogen deficiency-induced bone loss and its underlying mechanism remain unknown. In this study, we found that the abundance of Clostridium sporogenes (C. spor.) and its derived metabolite, indole propionic acid (IPA), were decreased in ovariectomized (OVX) mice. In vitro assays suggested that IPA suppressed osteoclast differentiation and function. At the molecular level, IPA suppressed receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced pregnane X receptor (PXR) ubiquitination and degradation, leading to increased binding of remaining PXR with P65. In vivo daily IPA administration or repeated C. spor. colonization protected against OVX-induced bone loss. To protect live bacteria from the harsh gastric environment and delay the emptying of orally administered C. spor. from the intestine, a C. spor.-encapsulated silk fibroin (SF) hydrogel system was developed, which achieved bone protection in OVX mice comparable to that achieved with repeated germ transplantation or daily IPA administration. Overall, we found that gut C. spor.-derived IPA was involved in estrogen deficiency-induced osteoclast overactivation by regulating the PXR/P65 complex. The C. spor.-encapsulated SF hydrogel system is a promising tool for combating postmenopausal osteoporosis without the disadvantages of repeated germ transplantation.
Assuntos
Reabsorção Óssea , Clostridium , Osteoclastos , Propionatos , Humanos , Feminino , Camundongos , Animais , Osteoclastos/metabolismo , Receptor de Pregnano X/metabolismo , Reabsorção Óssea/metabolismo , Osteogênese , Estrogênios/metabolismo , Indóis/metabolismo , Hidrogéis , Ligante RANK/metabolismo , Diferenciação CelularRESUMO
Variation in the molecular architecture significantly affects the electronic and supramolecular structure of biomolecular assemblies, leading to dramatically altered piezoelectric response. However, relationship between molecular building block chemistry, crystal packing and quantitative electromechanical response is still not fully understood. Herein, we systematically explored the possibility to amplify the piezoelectricity of amino acid-based assemblies by supramolecular engineering. We show that a simple change of side-chain in acetylated amino acids leads to increased polarization of the supramolecular arrangements, resulting in significant enhancement of their piezoelectric response. Moreover, compared to most of the natural amino acid assemblies, chemical modification of acetylation increased the maximum piezoelectric tensors. The predicted maximal piezoelectric strain tensor and voltage constant of acetylated tryptophan (L-AcW) assemblies reach 47 pm V-1 and 1719 mV m/N, respectively, comparable to commonly used inorganic materials such as bismuth triborate crystals. We further fabricated an L-AcW crystal-based piezoelectric power nanogenerator that produces a high and stable open-circuit voltage of over 1.4 V under mechanical pressure. For the first time, the illumination of a light-emitting diode (LED) is demonstrated by the power output of an amino acid-based piezoelectric nanogenerator. This work presents the supramolecular engineering toward the systematic modulation of piezoelectric response in amino acid-based assemblies, facilitating the development of high-performance functional biomaterials from simple, readily available, and easily tailored building blocks.
Assuntos
Aminoácidos , Triptofano , Acetilação , Materiais Biocompatíveis , BismutoRESUMO
Peptides can self-assemble into various hierarchical nanostructures through noncovalent interactions and form functional materials exhibiting excellent chemical and physical properties, which have broad applications in bio-/nanotechnology. The self-assembly mechanism, self-assembly morphology of peptide supramolecular architecture and their various applications, have been widely explored which have the merit of biocompatibility, easy preparation, and controllable functionality. Herein, we introduce the latest research progress of self-assembling peptide-based nanomaterials and review their applications in biomedicine and optoelectronics, including tissue engineering, anticancer therapy, biomimetic catalysis, energy harvesting. We believe that this review will inspire the rational design and development of novel peptide-based functional bio-inspired materials in the future.
Assuntos
Materiais Biomiméticos , Nanoestruturas , Materiais Biocompatíveis/química , Peptídeos/química , Nanoestruturas/química , NanotecnologiaRESUMO
Supramolecular packing dictates the physical properties of bio-inspired molecular assemblies in the solid state. Yet, modulating the stacking modes of bio-inspired supramolecular assemblies remains a challenge and the structure-property relationship is still not fully understood, which hampers the rational design of molecular structures to fabricate materials with desired properties. Herein, we present a co-assembly strategy to modulate the supramolecular packing of N-terminally capped alanine-based assemblies (Ac-Ala) by changing the amino acid chirality and mixing with a nonchiral bipyridine derivative (BPA). The co-assembly induced distinct solid-state stacking modes determined by X-ray crystallography, resulting in significantly enhanced electromechanical properties of the assembly architectures. The highest rigidity was observed after the co-assembly of racemic Ac-Ala with a bipyridine coformer (BPA/Ac-DL-Ala), which exhibited a measured Young's modulus of 38.8 GPa. Notably, BPA crystallizes in a centrosymmetric space group, a condition that is broken when co-crystallized with Ac-L-Ala and Ac-D-Ala to induce a piezoelectric response. Enantiopure co-assemblies of BPA/Ac-D-Ala and BPA/Ac-L-Ala showed density functional theory-predicted piezoelectric responses that are remarkably higher than the other assemblies due to the increased polarization of their supramolecular packing. This is the first report of a centrosymmetric-crystallizing coformer which increases the single-crystal piezoelectric response of an electrically active bio-inspired molecular assembly. The design rules that emerge from this investigation of chemically complex co-assemblies can facilitate the molecular design of high-performance functional materials comprised of bio-inspired building blocks.
Assuntos
Alanina , Aminoácidos , Cristalografia por Raios X , Estrutura MolecularRESUMO
The physical characteristics of supramolecular assemblies composed of small building blocks are dictated by molecular packing patterns in the solid-state. Yet, the structure-property correlation is still not fully understood. Herein, we report the unexpected cofacial to herringbone stacking transformation of a small aromatic bipyridine through co-assembly with acetylated glutamic acid. The unique solid-state structural transformation results in enhanced physical properties of the supramolecular organizations. The co-assembly methodology was further expanded to obtain diverse molecular packings by different bipyridine and acetylated amino acid derivatives. This study presents a feasible co-assembly approach to achieve the solid-state stacking transformation of supramolecular organization and opens up new opportunities to further explore the relationship between molecular arrangement and properties of supramolecular assemblies by crystal engineering.
Assuntos
Aminoácidos , Ácido Glutâmico , Conformação MolecularRESUMO
Modulation of the structural diversity of diphenylalanine-based assemblies by molecular modification and solvent alteration has been extensively explored for bio- and nanotechnology. However, regulation of the structural transition of assemblies based on this minimal building block into tunable supramolecular nanostructures and further construction of smart supramolecular materials with multiple responsiveness are still an unmet need. Coassembly, the tactic employed by natural systems to expand the architectural space, has been rarely explored. Herein, we present a coassembly approach to investigate the morphology manipulation of assemblies formed by N-terminally capped diphenylalanine by mixing with various bipyridine derivatives through intermolecular hydrogen bonding. The coassembly-induced structural diversity is fully studied by a set of biophysical techniques and computational simulations. Moreover, multiple-responsive two-component supramolecular gels are constructed through the incorporation of functional bipyridine molecules into the coassemblies. This study not only depicts the coassembly strategy to manipulate the hierarchical nanoarchitecture and morphology transition of diphenylalanine-based assemblies by supramolecular interactions but also promotes the rational design and development of smart hydrogel-based biomaterials responsive to various external stimuli.
Assuntos
Dipeptídeos , Substâncias Macromoleculares , Piridinas , Hidrogéis/química , Substâncias Macromoleculares/química , Nanoestruturas/química , Fenilalanina/química , Piridinas/química , Dipeptídeos/químicaRESUMO
Nanocatalytic tumor therapy is an emerging antitumor option that employs catalytically-active inorganic nanostructures to produce tumor-damaging reactive oxygen species. However, initiation of nanocatalytic reactions in the tumor intracellular environment is a challenge due to the reliance on acidic pH. By exploiting the pH-selective multifaceted catalytic activities of Prussian blue-based nanomaterials (PBNM) as well as the hyperglycolysis characteristics of tumors, it is demonstrated that blocking the monocarboxylate transporter 4 (MCT4)-mediated lactate effusion in tumor cells can reverse the pH gradient across the tumor cell membrane and cause rapid intracellular acidification as well as neutralization of the extracellular compartment, thus creating vulnerabilities for PBNM-based nanocatalytic therapies in situ while suppressing tumor stemness/metastasis in vivo. For this purpose, MCT4-inhibiting siRNAs are incorporated into reactivity-switchable PBNM-based nanocatalysts to initiate hydroxyl radical production. Meanwhile, ß-lapachone, a clinically-approved drug with H2 O2 -generating capabilities, is also integrated to sustain the nanocatalytic process. In contrast, the nanocatalyst shows no apparent toxicity to normal cells due to its catalase-like activities under neutral pH. This treatment strategy can inhibit tumor growth in mice at optimal safety as well as to suppress the cancer cell stemness and lung metastasis, suggesting the clinical translational potential of the findings.
Assuntos
Radical Hidroxila , Estresse Oxidativo , Animais , Linhagem Celular Tumoral , Transporte de Íons , Ácido Láctico , CamundongosRESUMO
Ferroptosis is a new form of regulated cell death with significant therapeutic prospect, but its application against drug-resistant tumor cells is challenging due to their ability to effuse antitumor agents via p-glycoprotein (P-gp) and anti-lipid peroxidation alkaline intracellular environment. Herein, an amorphous calcium phosphate (ACP)-based nanoplatform is reported for the targeted combinational ferroptosis/apoptosis therapy of drug resistant tumor cells by blocking the MCT4-mediated efflux of lactic acid (LA). The nanoplatform is fabricated through the biomineralization of doxorubicin-Fe2+ (DOX-Fe2+ ) complex and MCT4-inhibiting siRNAs (siMCT4) and can release them to the tumor cytoplasm after the hydrolysis of ACP and dissociation of DOX-Fe2+ in the acidic lysosomes. siMCT4 can inhibit MCT4 expression and force the glycolysis-generated lactic acid (LA) to remain in cytoplasm for rapid acidification. The nanoplatform-induced remodeling of the tumor intracellular environment can not only interrupt the ATP supply required for P-gp-dependent DOX effusion to enhance H2 O2 production, but also increase the overall catalytic efficiency of Fe2+ for the initiation and propagation of lipid peroxidation. These features could act in concert to enhance the efficacy of the combinational ferroptosis/chemotherapy and prolong the survival of tumor-bearing mice. This study may provide new avenues for the treatment of multidrug-resistant tumors.
Assuntos
Antineoplásicos , Ferroptose , Animais , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , CamundongosRESUMO
Clinically, inhibition of both bacterial infection and excessive inflammation is a crucial step for improved wound treatments. Herein, the fabrication of near-infrared-light (NIR)-activatable deoxyribonuclease (DNase)-carbon monoxide (CO)@mesoporous polydopamine nanoparticles (MPDA NPs) is demonstrated for efficient elimination of methicillin-resistant Staphylococcus aureus (MRSA) biofilms and the following anti-inflammatory activity. Specifically, thermosensitive CO-gas-releasing donors (CO releasing molecules, FeCO) are first encapsulated into MPDA NPs, followed by covalently immobilizing deoxyribonuclease I (DNase I) on the surfaces of MPDA NPs. DNase I can degrade the extracellular DNA in biofilms, which site specifically destroys the compactness of the biofilms. With NIR irradiation, DNase-CO@MPDA NPs display great photothermal ability, and further trigger on-demand delivery of bactericidal CO gas that can adequately permeate the impaired biofilms. Eventually, they achieve effective MRSA biofilm elimination in virtue of the synergistic effects of both DNase I participation and CO-gas-potentiated photothermal therapy. Importantly, the inflammatory responses of DNase-CO@MPDA NPs and NIR-treated wounds are simultaneously alleviated owing to the anti-inflammatory features of released CO. Finally, NIR-activatable DNase-CO@MPDA NPs accelerate the healing process of MRSA-biofilm-infected cutaneous wounds. Taken together, this phototherapeutic strategy displays great therapeutic potential in treating the formidable clinical problems caused by MRSA biofilms and the accompanying inflammation.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Nanopartículas , Antibacterianos , Biofilmes , Humanos , Inflamação , Raios Infravermelhos , Testes de Sensibilidade MicrobianaRESUMO
Implant-associated bacterial infections significantly impair the integration between titanium and soft tissues. Traditional antibacterial modifications of titanium implants are able to eliminate bacteria, but the resulting pro-inflammatory reactions are usually ignored, which still poses potential risks to human bodies. Here, a dual drug-loading system on titanium has been developed via the adhesion of a catechol motif-modified methacrylated gelatin hydrogel onto TiO2 nanotubes. Then synthesized CaO2 nanoparticles (NPs) are embedded into the hydrogel, and interleukin-4 (IL-4) is loaded into the nanotubes to achieve both antibacterial and anti-inflammatory properties. The dual drug-loading system can eliminate Staphylococcus aureus (S. aureus) rapidly, attributed to the H2 O2 release from CaO2 NPs. The potential cytotoxicity of CaO2 NPs is also remarkably reduced after being embedded into the hydrogel. More importantly, with the gradual release of IL-4, the dual drug-loading system is capable of modulating pro-inflammatory reactions by inducing M2 phenotype polarization of macrophages. In a subcutaneous infection model, the S. aureus contamination is effectively resolved after 2 days, and the resulting pro-inflammatory reactions are also inhibited after 7 days. Finally, the damaged tissue is significantly recovered. Taken together, the dual drug-loading system exhibits great therapeutic potential in effectively killing pathogens and inhibiting the resulting pro-inflammatory reactions.
Assuntos
Nanopartículas , Nanotubos , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Bactérias , Humanos , Peróxidos , Staphylococcus aureus , TitânioRESUMO
Liver tumor is difficult to cure for its high degree of malignancy and rapid progression characteristics. Ferroptosis as a new model of inducing cell death is expected to break the treatment bottleneck of liver tumors. Here, a strategy to induce ferroptosis in HepG2 cells with acid-degradable tumor targeted nanosheets Cu-Hemin-PEG-Lactose acid (Cu-Hemin-PEG-LA) is proposed. After highly ingested by HepG2 cells, Cu-Hemin-PEG-LA nanosheets are degraded by weak acid and release Cu(II) and hemin, which consuming intracellular glutathione (GSH) content and increasing the expression of heme oxygenase 1 (HMOX1) protein, respectively. Furthermore, the expression of glutathione peroxidase 4 protein (GPX4) is down-regulated by consumption intracellular GSH content via converting GSH into glutathione oxidized (GSSG), which is named the classical mode. The intracellular Fe2+ content is overloaded by the significant up-regulation of HMOX1 expression, which is denoted as nonclassical mode. The synergistic eï¬ect of classical and nonclassical mode increased the intracellular lipid reactive oxide species, induced the occurrence of ferroptosis and up-regulated the expression of BH3 interacting domain death agonist (BID), apoptosis-inducing factor (AIF), and endonuclease G proteins (EndoG). The synergistic strategy demonstrate the excellent ferroptosis induction ability and antitumor efficacy in vivo, which provides great potential for the clinical transformation of ferroptosis.
Assuntos
Ferroptose , Neoplasias Hepáticas , Compostos Ferrosos , Glutationa , Células Hep G2 , HumanosRESUMO
Ferroptosis is a new form of regulated cell death that shows promise for tumor treatment. Most current ferroptosis tumor therapies are based on the intrinsic pathological features of the malignancies, and it would be of clinical significance to develop ferroptosis-inducing strategies with improved tumor specificity and modulability. Here we report a polydopamine-based nanoplatform (FeII PDA@LAP-PEG-cRGD) for the efficient loading of Fe2+ and ß-lapachone (LAP), which could readily initiate ferroptosis in tumor cells upon treatment with near-infrared light. PDA nanostructures could generate mild hyperthermia under NIR irritation and trigger the release of the ferroptosis-inducing Fe2+ ions. The NIR-actuated photothermal effect would also activate cellular heat shock response and upregulate the downstream NQO1 via HSP70/NQO1 axis to facilitate bioreduction of the concurrently released ß-lapachone and enhance intracellular H2 O2 formation to promote the Fe2+ -mediated lipid peroxidation.
Assuntos
Antineoplásicos/farmacologia , Biopolímeros/farmacologia , Ferroptose/efeitos dos fármacos , Quelantes de Ferro/farmacologia , Nanopartículas/química , Naftoquinonas/farmacologia , Animais , Antineoplásicos/química , Biopolímeros/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Raios Infravermelhos , Quelantes de Ferro/química , Camundongos , Naftoquinonas/química , Tamanho da Partícula , Fototerapia , Propriedades de SuperfícieRESUMO
The chemotherapeutic efficacy of paclitaxel against hypoxic tumors is usually unsatisfactory, which is partially due to the so-called hypoxia-induced drug resistance. The mechanism of hypoxia-induced resistance is primarily associated with hypoxia-inducible factor 1α (HIF-1α), which is an oxygen-sensitive transcriptional activator coordinating the cellular response to hypoxia. Apigenin is a natural occurring HIF-1α inhibitor that can suppress the expression of HIF-1α through multiple pathways and reverse the hypoxia-induced resistance found in cancer cells. Here we report that the use of apigenin can suppress the HIF-1α expression in hypoxic tumors through the simultaneous inhibition of the AKT/p-AKT pathway and HSP90, which is beneficial for enhancing the anticancer activity of the co-administered paclitaxel. The potential synergistic effect of apigenin and paclitaxel was further validated on HepG2 cell line and tumor-bearing mouse models.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apigenina/farmacologia , Hipóxia Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Paclitaxel/farmacologia , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Apigenina/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Injeções Intravenosas , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Paclitaxel/administração & dosagem , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
The high lactate production rate in hepatocellular carcinoma cells (HCC) have a profound impact on their malignant properties. In adaptation to the enhanced lactate stress, lactate-effusing monocarboxylate transporter 4(MCT4) is usually overexpressed in a broad range of HCC subtypes. In this study, the MCT4-mediated lactate efflux in HCC was blocked using microRNA-145(miR-145), which would force the endogenously generated lactate to accumulate within tumor cells in a self-regulated manner, resulting in the acidification of the cytoplasmic compartment as well as partial neutralization for pH in the tumor extracellular environment. Evaluations on multiple representative HCC subtypes (HepG2, Hep3B and HuH7) suggested that the disrupted pH homeostasis would amplify the lactate stress to initiate HCC apoptosis, while at the same time also suppressing their migration and invasion abilities. Moreover, safety tests on 7702â¯cells and living animals revealed that MCT4-blockade treatment has no cytotoxicity against healthy cells/tissues. The results indicate the MCT4-inhibition-induced disruption of tumor intracellular pH holds promise as a therapy against not only HCC, but a broader spectrum of MCT4-overexpressing hyperglycolytic tumors.
Assuntos
Apoptose/fisiologia , Carcinoma Hepatocelular/metabolismo , Homeostase/fisiologia , Neoplasias Hepáticas/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Citoplasma/metabolismo , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Hepáticas/patologia , Camundongos , MicroRNAs/metabolismoRESUMO
Photothermal conversion agents (PTCAs) based on π-conjugated polymers are promising for cancer therapy, but the alteration of bandgap energies toward boosted photothermal properties remains challenging. Herein, polymer PTCAs with heterojunctions of a binary optical component are developed by interface hybridization on porous particles. Specifically, polypyrrole (PPy) nanodomains are successfully hosted on the wet-adhesive surface of mesoporous polydopamine nanoparticles through the loading and polymerization of pyrrole in the confined pore space (≈5.0 nm). The near-infrared absorbing polymers in the heterojunctions possess similar five-membered heterocyclic rings and can interact mutually to generate photoinduced electron transfer (PET). Such a large-area optoelectronic interaction progressively reduces the bandgap energy (down to 0.56 eV) by increasing the doped amount of PPy, which consequently enhances the extinction coefficient and photothermal conversion efficiency by 4.6- and 2.2-fold, respectively. Notably, the hybrid PTCA exhibits good biocompatibility, photocytotoxicity, and great potential for cancer therapy.
Assuntos
Indóis/química , Nanopartículas/química , Polímeros/química , Pirróis/química , Temperatura , Tamanho da Partícula , Processos Fotoquímicos , Porosidade , Propriedades de SuperfícieRESUMO
Combination chemotherapy with a modulator and a chemotherapeutic drug has become one of the most promising strategies for the treatment of multidrug resistance (MDR) in cancer therapy. However, the development of nanocarriers with a high payload and sequential release of therapeutic agents poses a significant challenge. In this work, we report a type of hybrid nanocarriers prepared by polydopamine (PDA) mediated integration of the mesoporous MSN core and the microporous zeolite imidazolate frameworks-8 (ZIF-8) shell. The nanocarriers exploit storage capacities for drugs based on the high porosity and molecular sieving capabilities of ZIF-8 for sequential drug release. Particularly, large amounts of an anticancer drug (DOX, 607 µg mg-1) and a MDR inhibitor curcumin (CUR, 778 µg mg-1) were sequentially loaded in the mesoporous core via π-π stacking interactions mediated by PDA and in the microporous shell via the encapsulation during ZIF-8 growth. The sustained release of DOX was observed to follow earlier and faster release of CUR by acid-sensitive dissolution of the ZIF-8 shell. Furthermore, the nanoparticles showed good biocompatibility and effective cellular uptake in in vitro evaluations using drug-resistant MCF-7/ADR cancer cells. More importantly, the preferentially released CUR inhibited the drug efflux function of the membrane P-glycoprotein (P-gp), which subsequently facilitated the nuclear transportation of DOX released from the PDA-MSN core, and, in turn, the synergistic effects on killing MDR cancer cells. The hybrid mesoporous-microporous nanocarrier holds great promise for combination chemotherapy applications on the basis of sequential drug release.
Assuntos
Antineoplásicos/farmacologia , Portadores de Fármacos/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Antineoplásicos/uso terapêutico , Curcumina/farmacologia , Curcumina/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Combinação de Medicamentos , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Células MCF-7 , Nanopartículas/química , Neoplasias/patologia , PorosidadeRESUMO
In this study, a type of bacteria enzyme-triggered antibacterial surface with a controlled release of Ag ions was developed. Firstly, chitosan-silver nanocomposites (Chi@Ag NPs) were in situ synthesized via using ascorbic acid as reducing agent. Chi@Ag NPs were characterized by transmission electron microscopy, ultraviolet-visible spectroscopy, X-ray diffraction and X-ray photoelectron spectroscopy. Subsequently, Chi@Ag NPs and hyaluronic acid (HA) were used to fabricate antibacterial composite coating via Layer-by-Layer (LBL) self-assembly method. The successful construction of Chi@Ag NPs/HA composite coating was confirmed by scanning electron microscopy, energy dispersive spectroscopy and contact angle measurements, respectively. Then, the amount of released Ag ion was analyzed by inductively coupled plasma atomic emission spectrometry, which demonstrated that the release of Ag ions from the surface could be triggered by enzyme (e.g. hyaluronidase). A series of antibacterial tests in vitro, including zone of inhibition test, bacterial viability assay, antibacterial rate measurement and bacteria adhesion observation, demonstrated that the enzyme-responsive surface could inhibit the growth of bacteria. On the whole, this study provides an alternative approach for the fabrication of antibacterial surfaces on synthetic materials in various fields with the minimal side effects on surrounding environment and human body.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Substitutos Ósseos/química , Fosfatos de Cálcio/química , Materiais Revestidos Biocompatíveis/química , Colágeno/química , Gelatina/química , Microscopia Eletrônica de Varredura , Nanocompostos , Propriedades de Superfície , Resistência à TraçãoRESUMO
The combination of fluorophore-labelled single-strand DNA probes and nanomaterial quenchers has shown great potential in miRNA detection. The development of advanced detection systems by understanding and controlling the fluorescence quenching/recovery via nanoquenchers' microstructures and local morphologies is an attractive area warranting further investigations. Inspired by nanopore sequencing, we present a novel miRNA sensing strategy using fluorophore-labeled DNA as probes and a type of large-pore-sized mesoporous polydopamine nanoparticles (MPDA-L, 70 nm in diameter) as fluorescence quenchers. It is revealed that the quenching efficiency of MPDA-L towards the fluorophore labelled on the probe, reached more than 99% at a relatively low particle concentration. Moreover, the mesopores effectively protected the probe DNA from cleavage by DNase I which was used for signal amplification. Sensitive detection of miRNA with a low detection limit of 32-40 pM, as well as a linear detection range of up to 5 nM, was realized by the mesopore effects via a greatly improved differential affinity of ssDNA and the probe-miRNA heteroduplex toward the surface of nanoquenchers. Interestingly, enhanced DLVO (Derjaguin-Landau-Verwey-Overbeek) repulsion generated inside the pore surface by the negative surface-curvature effect correlates with the improved duplex detachment and fluorescence recovery. The developed strategy can be successfully applied to quantify down-regulated let-7a and up-regulated miRNA-21 in different types of cancer cells by using total RNA samples from cell lysate. These findings are expected to inspire strategies and pave a way for utilizing porous nanomaterials for constructing miRNA detection systems.