RESUMEN
Biosynthesized gold nanoparticles (AuNPs) are highly attracted as a biocompatible nanodrug to treat various diseased conditions in humans. In this study, phytochemical tannic acid-mediated AuNPs (TA-AuNPs) are successfully synthesized and tested for antibacterial and antibiofilm activity against dental biofilm-forming Streptococcus mutans biofilm. The synthesized TA-AuNPs are appeared as spherical in shape with an average size of 19 nm. The antibacterial potential of TA-AuNPs was evaluated using ZOI and MIC measurements; while, antibiofilm efficacy was measured by checking the eradication of preformed biofilm on the tooth model. The ZOI and MIC values for TA-AuNPs are 25 mm in diameter and 4 µg/mL, respectively. The MTT assay, CLSM, and SEM results demonstrate that the preformed S. mutans biofilm is completely eradicated at 4xMIC (16 µg/mL) of TA-AuNPs. Finally, the present study reveals that the synthesized TA-AuNPs might be a great therapeutic drug to treat dental biofilm-forming bacterium S. mutans.
Asunto(s)
Caries Dental , Nanopartículas del Metal , Polifenoles , Humanos , Oro/farmacología , Streptococcus mutans , Antibacterianos/farmacología , Biopelículas , Caries Dental/tratamiento farmacológico , Pruebas de Sensibilidad MicrobianaRESUMEN
NO gas therapy is a supplementary approach for tumor treatment due to the advantages of minimal invasion, little drug resistance, low side effect and amplified efficacy. l-Arginine (L-Arg), a natural NO source with good biocompatibility, can release NO under the stimulation of H2O2 in tumor microenvironment. However, the conventional l-Arg delivery systems via noncovalent loading usually lead to inevitable premature leakage of nano-cargos during blood circulation. In this work, an efficient l-Arg self-delivery supramolecular nanodrug (SDSND) for tumor treatment is demonstrated by combining Mannich reaction and π-π stacking. l-Arg links to (-)-epigallocatechin gallate (EGCG) with the assistance of formaldehyde through Mannich reaction, and then assembles into nanometer-sized particles via π-π stacking. The guanidine group of l-Arg and the phenolic hydroxyl groups of EGCG are preserved in the SDSNDs, which allows for accomplishing gas therapy by provoking tumor cell apoptosis and combining with EGCG to amplify apoptosis, respectively. In addition, the SDSNDs exhibit high biocompatibility and avoid the premature leakage of l-Arg in blood circulation, providing an alternative l-Arg delivery system for NO gas therapy. STATEMENT OF SIGNIFICANCE: NO gas therapy has attracted emerging interest in tumor treatment. However, the controlled NO release and the avoidance of premature leakage of NO donors remain challenging. In this work, L-Arginine (L-Arg) self-delivery supramolecular nanodrug for efficient tumor therapy is demonstrated through the Mannich reaction of L-Arg, (-)-epigallocatechin gallate (EGCG) and formaldehyde. Stimulated by tumor microenvironment, the guanidine groups of L-Arg allow for accomplishing NO release and thus provoking tumor cell apoptosis. The nanodrug also avoids the premature leakage of L-Arg in blood circulation. Moreover, the preserved phenolic hydroxyl groups of EGCG combine with L-Arg to amplify apoptosis. The nanodrug exhibits high biocompatibility and good therapeutic effect, providing an alternative L-Arg delivery system for NO gas therapy.
Asunto(s)
Nanopartículas , Neoplasias , Humanos , Peróxido de Hidrógeno/farmacología , Neoplasias/tratamiento farmacológico , Apoptosis , Nanopartículas/uso terapéutico , Arginina/farmacología , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Ferroptosis is a non-apoptotic programmed cell death caused by the accumulation of lipid peroxide. System Xc-/glutathione peroxidase 4 (GPX4) axis and iron axis are two main pathways regulating ferroptosis. Simultaneously, multiple pathways are also involved in the ferroptosis regulation. Ferroptosis is an intense area of the current study. With the improvement of the regulatory mechanisms that underlie ferroptosis, a variety of drugs associated with ferroptosis have been discovered and developed for cancer therapy. Among them, traditional drugs were developed initially. Small molecule compounds that regulate ferroptosis signaling pathway and iron complexes that promote the Fenton reaction have become important drugs for inducing ferroptosis. In recent years, the emerging development of nanotechnology has promoted the research of ferroptosis nanodrugs. Iron-based nanomaterials are extensively tested as ferroptosis-inducing agents. Furthermore, nanoscale drug delivery systems offer a suitable scaffold for traditional drug therapies. Traditional drugs and nanodrugs are complementary, each with their own strengths and limitations. This review describes the latest studies on the regulation of ferroptosis in tumor cells and focuses on the entanglement between traditional drugs and nanodrugs. To conclude, the challenges and perspectives in this field are put forward.
Asunto(s)
Ferroptosis , Nanopartículas , Especies Reactivas de Oxígeno/metabolismo , Hierro , Nanopartículas/uso terapéuticoRESUMEN
Functional nanomaterials as nanodrugs based on the self-assembly of inorganics, polymers, and biomolecules have showed wide applications in biomedicine and tissue engineering. Ascribing to the unique biological, chemical, and physical properties of peptide molecules, peptide is used as an excellent precursor material for the synthesis of functional nanodrugs for highly effective cancer therapy. Herein, recent progress on the design, synthesis, functional regulation, and cancer bioimaging and biotherapy of peptide-based nanodrugs is summarized. For this aim, first molecular design and controllable synthesis of peptide nanodrugs with 0D to 3D structures are presented, and then the functional customization strategies for peptide nanodrugs are presented. Then, the applications of peptide-based nanodrugs in bioimaging, chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT) are demonstrated and discussed in detail. Furthermore, peptide-based drugs in preclinical, clinical trials, and approved are briefly described. Finally, the challenges and potential solutions are pointed out on addressing the questions of this promising research topic. This comprehensive review can guide the motif design and functional regulation of peptide nanomaterials for facile synthesis of nanodrugs, and further promote their practical applications for diagnostics and therapy of diseases.
Asunto(s)
Nanopartículas , Nanoestructuras , Neoplasias , Humanos , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Péptidos/química , Nanoestructuras/química , Terapia Biológica , Nanopartículas/uso terapéutico , Nanopartículas/químicaRESUMEN
Targeted synergistic therapy has broad prospects in tumor treatments. Here, a multi-functional nanodrug GDYO-CDDP/DOX@DSPE-PEG-MTX (GCDM) based on three traditional anticancer drugs (doxorubicin (DOX), cisplatin (CDDP) and methotrexate (MTX)) modified graphdiyne oxide (GDYO) is described, for diagnosis and targeted cancer photo-chemo synergetic therapy. In this system, for the first time, these three traditional anti-cancer drugs have played new roles and can reduce multidrug resistance through synergistic anti-tumor effects. Cisplatin can be hybridized with GDYO to form a multifunctional and well-dispersed three-dimensional framework, which can not only be used as nano-drug carriers to achieve high drug loading rates (40.3%), but also exhibit excellent photothermal conversion efficiency (47%) and good photodynamic effects under NIR irradiation. Doxorubicin (DOX) is loaded onto GDYO-CDDP through π-π stacking, which is used as an anticancer drug and as a fluorescent probe for nanodrug detection. Methotrexate (MTX) can be applied in tumor targeting and play a role in synergistic chemotherapy with DOX and CDDP. The synthesized multi-functional nanodrug GCDM has good biocompatibility, active targeting, long-term retention, sustained drug release, excellent fluorescence imaging capabilities, and remarkable photo-chemo synergistic therapeutic effects.
Asunto(s)
Grafito , Nanopartículas , Neoplasias , Línea Celular Tumoral , Doxorrubicina/farmacología , Liberación de Fármacos , Neoplasias/tratamiento farmacológico , FototerapiaRESUMEN
The chirality of nanoparticles directly influences their transport and biological effects under physiological conditions, but the details of this phenomenon have rarely been explored. Herein, chiral GSH-anchored selenium nanoparticles (G@SeNPs) are fabricated to investigate the effect of their chirality on their transport and antioxidant activity. G@SeNPs modified with different enantiomers show opposite handedness with a tunable circular dichroism signal. Noninvasive positron emission tomography imaging clearly reveals that 64 Cu-labeled l-G@SeNPs experience distinctly different transport among the major organs from that of their d-and dl-counterparts, demonstrating that the chirality of the G@SeNPs influences the biodistribution and kinetics. Taking advantage of the strong homologous cell adhesion and uptake, l-G@SeNPs have been shown here to effectively prevent oxidation damage caused by palmitic acid in insulinoma cells.
Asunto(s)
Antioxidantes/química , Glutatión/química , Nanopartículas/química , Selenio/química , Animales , Antioxidantes/farmacocinética , Apoptosis/efectos de los fármacos , Transporte Biológico , Adhesión Celular/efectos de los fármacos , Medios de Contraste/química , Radioisótopos de Cobre/química , Humanos , Espectrometría de Masas , Ratones , Nanopartículas/metabolismo , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Tomografía de Emisión de Positrones , Ratas , Selenio/orina , Estereoisomerismo , Distribución TisularRESUMEN
Mitochondria are ideal anti-tumor target due to mitochondria's central regulation role in cell apoptosis and tumor resistance to apoptosis. There are several challenges for mitochondrial targeting drug delivery, including complex multistep preparations, low drug- loading and systemic toxicity from the carriers. To address these issues, we firstly constructed mitochondria-targeting nanodrugs self-assembled from 9-O-octadecyl substituted berberine derivative (BD) using simple nano-precipitation approach. BD-based nanodrugs were modified by DSPE-PEG2000 (distearylphosphatidylethanolamine- methoxypolyethylene glycol 2000) to increase stability. Negatively charged hyaluronic acid (HA) was further coated to conceal positive charges and achieve tumor targeting. PEG and HA dually modified BD NDs (HA/PEG/BD NDs) were prepared with surface charge of -25.8â¯mV and high drug loading >70%. The degradation of HA by hyaluronidase (HAase) at tumor tissue allowed the exposure of the positively charged PEG/BD NDs to the cells, which is beneficial for cell uptake and further lysosome escape and mitochondrial targeting. Then, HA/PEG/BD NDs were investigated to induce apoptosis through dissipating mitochondria membrane potential, releasing cytochrome C, increasing the activities of caspase 9/3, activating the pro-apoptotic Bax, suppressing the anti-apoptotic Bcl-2 and upregulating ROS levels. In the A549 xenografted tumor model, HA/PEG/BD NDs exhibited obvious tumor cell mitochondrial targeting and significant anti-tumor efficacy. Overall, comparing to conventional nanoparticles, mitochondrial targeting HA/PEG/BD NDs provide a new strategy for cancer treatment with enhanced drug-loading, relatively simplified preparation processes and reduced carrier toxicities.
Asunto(s)
Antineoplásicos/administración & dosificación , Berberina/análogos & derivados , Berberina/administración & dosificación , Sistemas de Liberación de Medicamentos , Neoplasias Pulmonares/tratamiento farmacológico , Nanopartículas/administración & dosificación , Células A549 , Animales , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Berberina/química , Citocromos c/metabolismo , Liberación de Fármacos , Femenino , Humanos , Ácido Hialurónico/administración & dosificación , Ácido Hialurónico/química , Neoplasias Pulmonares/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Mitocondrias/fisiología , Nanopartículas/química , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Curcumin (CUR) is a natural diketone with diverse bioactivities of inhibiting angiogenesis and tumor growth. However, its clinical application for cancer treatment was severely hindered by poor aqueous solubility and chemical instability. To overcome these drawbacks and achieve enhanced antitumor efficiency, low molecular weight heparin (LMWH) was conjugated to CUR via the one-step esterification reaction to yield LMWH-CUR (LCU) nanodrugs with the size of 180â¯nm, which exhibited enhanced accumulation within tumor site by EPR effect and long circulating capacity by LMWH hydrophilic shell. The solubility of conjugated CUR was increased to 0.12â¯mg/mL (equivalent of CUR) in comparison with 0.006â¯mg/mL of free CUR. The bioactivities of CUR were guaranteed because of the improved stability of LCU nanodrugs in low pH condition. Moreover, the stronger anti-angiogenesis efficacy of LCU nanodrugs than LMWH monotherapy was also verified. Notably, at a rather low dose of equivalent LMWH (5â¯mg/kg) and CUR (0.3â¯mg/kg), the tumor inhibition rate of LCU nanodrugs were much higher than that of LMWH (10 times) and LMWH plus CUR mixture (3.8 times) respectively, indicating its excellent in vivo antitumor efficacy. Overall, our study managed to obtain the novel nanodrugs with potent anti-angiogenesis and antitumor effects whereas avoiding tedious and complicated synthetic procedures. These results also suggested that LCU nanodrugs could be considered as a promising targeted delivery system for cancer treatment.
Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Antineoplásicos/administración & dosificación , Curcumina/administración & dosificación , Nanopartículas/administración & dosificación , Neoplasias/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Antineoplásicos/uso terapéutico , Coagulación Sanguínea/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Curcumina/uso terapéutico , Combinación de Medicamentos , Estabilidad de Medicamentos , Eritrocitos/efectos de los fármacos , Eritrocitos/fisiología , Hemólisis/efectos de los fármacos , Células Hep G2 , Humanos , Ratones , Nanopartículas/uso terapéutico , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Conejos , Carga Tumoral/efectos de los fármacosRESUMEN
Arsenic trioxide (ATO, As2 O3 ) is currently used to treat acute promyelocytic leukemia. However, expanding its use to include high-dose treatment of other cancers is severely hampered by serious side effects on healthy organs. To address these limitations, we loaded ATO onto folate (FA)-labeled human serum albumin (HSA) pretreated with glutathione (GSH) based on the low pH- and GSH-sensitive arsenic-sulfur bond, and we termed the resulting smart nanodrug as FA-HSA-ATO. FA-HSA-ATO could specifically recognize folate receptor-ß-positive (FRß+) chronic myeloid leukemia (CML) cells, resulting in more intracellular accumulation of ATO. Furthermore, the nanodrug could upregulate FRß expression in CML cancer cells and xenograft tumor model, facilitating even more recruitment and uptake of FRß-targeting drugs. Inâ vitro and inâ vivo experiments indicate that the nanodrug significantly alleviates side effects and improves therapeutic efficacy of ATO on CML and xenograft tumor model.
Asunto(s)
Antineoplásicos/farmacología , Trióxido de Arsénico/farmacología , Receptor 2 de Folato/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Nanopartículas/química , Albúmina Sérica Humana/química , Animales , Antineoplásicos/química , Trióxido de Arsénico/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Receptor 2 de Folato/metabolismo , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Ratones , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Relación Estructura-ActividadRESUMEN
Multimodal imaging-guided synergistic combination therapy has shown great potential for cancer treatment. However, the nanocarrier-based theranostic systems suffer from batch-to-batch variation, complexity of multicomponent, poor drug loading, and carrier-related toxicity issues. To address these issues, herein we developed a novel carrier-free theranostic system with nanoscale characteristics for near-infrared fluorescence (NIRF) and photoacoustic (PA) dual-modal imaging-guided synergistic chemo-photothermal therapy (PTT). Indocyanine green (ICG) and epirubicin (EPI) could co-self-assemble into small molecular nanoparticles (NPs) in aqueous solution without any molecular precursor or excipient via collaborative interactions (electrostatic, π-π stacking, and hydrophobic interactions). The exceptionally high dual-drug loading (â¼92wt%) ICG-EPI NPs showed good physiological stability, preferable photothermal response, excellent NIRF/PA imaging properties, pH-/photo-responsive drug release behavior, and promoted cellular endocytosis compared with free ICG or EPI. Importantly, the ICG-EPI NPs showed excellent tumor targeting ability with high spatial resolution and deep penetration via in vivo NIRF/PA dual-modal imaging. Moreover, in comparison with individual chemotherapy or PTT, the combinational chemo-PTT therapy of ICG-EPI NPs with NIR laser irradiation synergistically induced apoptosis and death of cancer cells in vitro, and showed synergistic chemo-PTT efficiency in vivo as evidenced by highly efficient tumor ablation. Furthermore, the ICG-EPI NPs exhibited inappreciable toxicity. This co-self-assembly of both FDA-approved agents provides a safe and "Molecular economical" strategy in the rational design of multifunctional nano-theranostic systems for real-time self-monitoring intracellular drug delivery and targeting multimodal imaging-guided synergistic combination therapy.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/terapia , Colorantes/administración & dosificación , Epirrubicina/administración & dosificación , Verde de Indocianina/administración & dosificación , Nanomedicina Teranóstica/métodos , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Colorantes/química , Terapia Combinada/métodos , Sistemas de Liberación de Medicamentos/métodos , Epirrubicina/química , Epirrubicina/uso terapéutico , Femenino , Humanos , Hipertermia Inducida/métodos , Verde de Indocianina/química , Células MCF-7 , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Moleculares , Nanopartículas/administración & dosificación , Nanopartículas/química , Nanopartículas/uso terapéutico , Imagen Óptica/métodos , Técnicas Fotoacústicas/métodos , Fototerapia/métodosRESUMEN
Photodynamic therapy (PDT) involves the action of photons on photosensitive molecules, where atomic oxygen or OH(-) molecular species are locally released on pathogenic human cells, which are mainly carcinogenic, thus causing cell necrosis. The efficacy of PDT depends on the local nanothermodynamic conditions near the cell/nanodrug system that control both the level of intracellular translocation of nanoparticles in the pathogenic cell and their agglomeration on the cell membrane. Dendrimers are considered one of the most effective and promising drug carriers because of their relatively low toxicity and negligible activation of complementary reactions. Polyamidoamine (PAMAM) dendrite delivery of PDT agents has been investigated in the last few years for tumour selectivity, retention, pharmacokinetics and water solubility. Nevertheless, their use as drug carriers of photosensitizing molecules in PDT for cardiovascular disease, targeting the selective necrosis of macrophage cells responsible for atheromatous plaque growth, has never been investigated. Furthermore, the level of aggregation, translocation and nanodrug delivery efficacy of PAMAM dendrimers or PAMAM/zinc phthalocyanine (ZnPc) conjugates on human atheromatous tissue and endothelial cells is still unknown. In this work, the aggregation of PAMAM zero generation dendrimers (G0) acting as drug delivery carriers, as well as conjugated G0 PAMAM dendrimers with a ZnPc photosensitizer, to symptomatic and asymptomatic human carotid tissues was investigated by using atomic force microscopy (AFM). For the evaluation of the texture characteristics of the AFM images, statistical surface morphological and fractal analytical methodologies and Minkowski functionals were used. All statistical quantities showed that the deposition of nanodrug carriers on healthy tissue has an inverse impact when comparing to the deposition on atheromatous tissue with different aggregation features between G0 and G0/ZnPc nanoparticles and with considerably larger G0/ZnPc aggregations on the atheromatous plaque. The results highlight the importance of using PAMAM dendrimer carriers as a novel and promising PDT platform for atherosclerosis therapies.