RESUMEN
The development of nonviral dendritic polymers with a simple molecular backbone and great gene delivery efficiency to effectively tackle cancer remains a great challenge. Phosphorus dendrimers or dendrons are promising vectors due to their structural uniformity, rigid molecular backbones, and tunable surface functionalities. Here, we report the development of a new low-generation unsymmetrical cationic phosphorus dendrimer bearing 5 pyrrolidinium groups and one amino group as a nonviral gene delivery vector. The created AB5-type dendrimers with simple molecular backbone can compress microRNA-30d (miR-30d) to form polyplexes with desired hydrodynamic sizes and surface potentials and can effectively transfect miR-30d to cancer cells to suppress the glycolysis-associated SLC2A1 and HK1 expression, thus significantly inhibiting the migration and invasion of a murine breast cancer cell line in vitro and the corresponding subcutaneous tumor mouse model in vivo. Such unsymmetrical low-generation phosphorus dendrimers may be extended to deliver other genetic materials to tackle other diseases.
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Dendrímeros , MicroARNs , Neoplasias , Animales , Ratones , Dendrímeros/química , Vectores Genéticos , MicroARNs/genética , Técnicas de Transferencia de Gen , Cationes , FósforoRESUMEN
Polydopamine (PDA)-based nanostructures are used for biomedical purposes. A hybrid drug nanocarrier based on a PDA decorated with polyamidoamine (PAMAM) dendrimers G 3.0 (DG3) followed by a connection with glycol (PEG) moieties, folic acid (FA), and drug doxorubicin (DOX) was used for combined chemo- and photothermal therapy (CT-PTT) of liver cancer. Oxidative stress plays a crucial role in the development of cancer, and PDA seems to have the ability to both donate and accept electrons. We investigated oxidative stress in organs by evaluating oxidative stress markers in vivo. In the liver, the level of reduced glutathione (GSH) was lower and the level of Trolox equivalent antioxidant capacity (TEAC) was higher in the group receiving doxorubicin encapsulated in PDA nanoparticles with phototherapy (PDA@DG3@PEG@FA@DOX + PTT) compared to the control group. The concentration of thiobarbituric acid reactive substances (TBARS) in livers, was higher in the group receiving PDA coated with PAMAM dendrimers and functionalized with PEG and FA (PDA@DG3@PEG@FA) than in other groups. Markers in the brain also showed lower levels of GSH in the PDA@DG3@PEG@FA group than in the control group. Markers of oxidative stress indicated changes in the organs of animals receiving PDA nanoparticles with PAMAM dendrimers functionalized with FA in CT-PTT of liver cancer under in vivo conditions. Our work will provide insights into oxidative stress, which can be an indicator of the toxic potential of PDA nanoparticles and provide new strategies to improve existing therapies.
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Dendrímeros , Neoplasias Hepáticas , Nanopartículas , Humanos , Ratones , Animales , Dendrímeros/química , Terapia Fototérmica , Xenoinjertos , Doxorrubicina/química , Nanopartículas/química , Fototerapia , Neoplasias Hepáticas/tratamiento farmacológico , Estrés Oxidativo , Línea Celular TumoralRESUMEN
Berberine is an anticancer medication that generates side effects due to its hydrophobicity and low cellular promiscuity as well as high dose requirement. Thus, have to prepare PEGylated dendrimer conjugates which increases the targeting and release of chemotherapeutic drugs at the tumor site although falling the adverse side effects. The circulation time of drug is enhanced by PEGylation. It is the covalent attachment of PEG to therapeutic protein or any molecule. PEGylated berberine dendrimer was prepared by biotinylation cross linking method and characterized by particle size, zeta potential, entrapment efficiency, in vitro release and stability study. The Structure validation of berberine before and after grafting was confirmed by FTIR and NMR spectroscopy. Further prepared PEGylated complex were proceeded for the cellular uptake study in AMJ-13, and BT-20 cells line by fluorescent microscopy study and MTT assay cytotoxicity study in MCF-7 cell line. The prepared PEGylated formulation showed nanometric size, desired zeta potential, and 69.56 ± 23% entrapment efficiency. The prepared PEGylated particle showed 70.23% release at 72 h with good stability at 90 days. The cellular uptake of formulation was highly appreciable which is clearly observed in AMJ-13 and BT-20 cells line. In comparison to pure drug, developed formulation has 10.8 M high efficiency for breast cancer cell line. PEGylation is easy and reasonable way, as it requires lesser time and is proved to be superior technique for treatment of cancer.
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Berberina , Dendrímeros , Humanos , Dendrímeros/química , Portadores de Fármacos/química , Polietilenglicoles/químicaRESUMEN
The structure of phosphorus-containing dendrimers has been studied by IR spectroscopy and optical polarization microscopy. The repeating units of dendrimer molecules are mesogens. This property arises from the conjugation of the aromatic ring and the hydrazone group. An analysis of the IR spectra showed that, with an increase in the generation number, the width of the stretching vibration bands ν(PN) and ν(PO) increases. Difficulties in packing molecules of higher generations cause conformational diversity. The shape of the dendrimer molecules was determined by analyzing the increments of dipole moments. Additionally, the modeling of the stacking of repeating links was performed. The spherical model of molecules does not satisfy the experimental dipole moments of the dendrimers. The flat disk model is more suitable for explaining step changes in dipole moments. The liquid-crystalline ordering of dendrimers under the action of applied pressure was found. With simultaneous heating and uniaxial compression, optical anisotropy appears in dendrimers. It is associated with the formation of liquid-crystalline order. However, a thermodynamically stable liquid-crystalline phase is not formed in this case. Dendrimers most likely have disk-shaped molecules.
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Dendrímeros , Cristales Líquidos , Fósforo/química , Dendrímeros/química , Cristales Líquidos/química , Conformación Molecular , Espectrofotometría InfrarrojaRESUMEN
Piperine (PIP) is a neuroprotective phytomedicine that has profound acetylcholine esterase and reactive oxygen species inhibition effect in Alzheimer's disease (AD) model. However, the oral delivery of PIP is limited by poor aqueous solubility and low bioavailability in systemic circulation. To improve the PIP bioavailability, the polyamidoamine (PAMAM) G4 dendrimer is grafted with tocopheryl polyethylene glycol succinate-1000 (TPGS) through carbodiimide chemistry to form TPGS-PAMAM conjugate. The TPGS-PAMAM coupling was confirmed through proton NMR and FTIR techniques. PIP was encapsulated in the TPGS-PAMAM through solvent diffusion method to form PIP-TPGS-PAMAM. The particle size for PIP-TPGS-PAMAM found the less than 50 nm, whereas entrapment efficiency found to 87 ± 3.5% and 10.6 ± 2.9% drug loading. The powder differential scanning calorimetry and powder X-ray diffraction characterization were employed to evaluate the amorphous encapsulation of the PIP in TPGS-PAMAM. The PIP-TPGS-PAMAM stability was studied in the gastric fluids which showed no drastic difference in particle size and encapsulation efficiency compared to PIP-PAMAM. The in vitro release analysis revealed 37 ± 4.1% PIP release from the PIP-TPGS-PAMAM matrix, and 71 ± 4.9% PIP release from the PIP-PAMAM dendrimer was observed in 48 h. The single-dose oral gavage to Wistar rats of PIP-TPGS-PAMAM showed the AUC0-∞ 14.38 µg/mL.h, Cmax 7.77 ± 1.65 µg/mL, Tmax, 1.6 ± 0.18 h, and half-life 3.47 ± 0.64 h for PIP in systemic circulation. PIP-PAMAM and free PIP showed significantly poor AUC0-∞ compared to PIP-TPGS-PAMAM. The brain uptake studies revealed PIP-TPGS-PAMAM treated group showed 2.2 ± 0.37 µg/g PIP content compared to free PIP administered group which was 0.4 ± 0.10 µg/g. Therefore, PIP-TPGS-PAMAM can offer excellent prospect for the delivery hydrophobic drugs to brain in AD.
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Dendrímeros , Alcaloides , Animales , Benzodioxoles , Encéfalo , Dendrímeros/química , Portadores de Fármacos/química , Tamaño de la Partícula , Piperidinas , Poliaminas , Polietilenglicoles/química , Alcamidas Poliinsaturadas , Polvos , Ratas , Ratas Wistar , Succinatos , Ácido Succínico , Vitamina E/químicaRESUMEN
Conventional small molecular chemical drugs always have challenging limitations in cancer therapy due to their high systemic toxicity and low therapeutic efficacy. Nanotechnology has been applied in drug delivery, bringing new promising potential to realize effective cancer treatment. In this context, we develop here a new nanomicellar drug delivery platform generated by amphiphilic phosphorus dendrons (1-C17G3.HCl), which could form micelles for effective encapsulation of a hydrophobic anticancer drug doxorubicin (DOX) with a high drug loading content (42.4%) and encapsulation efficiency (96.7%). Owing to the unique dendritic rigid structure and surface hydrophilic groups, large steady void space of micelles can be created for drug encapsulation. The created DOX-loaded micelles with a mean diameter of 26.3 nm have good colloidal stability. Strikingly, we show that the drug-free micelles possess good intrinsic anticancer activity and act collectively with DOX to take down breast cancer cells in vitro and the xenografted tumor model in vivo through upregulation of Bax, PTEN, and p53 proteins for enhanced cell apoptosis. Meanwhile, the resulting 1-C17G3.HCl@DOX micelles significantly abolish the toxicity relevant to the free drug. The findings of this study demonstrate a unique nanomicelle-based drug delivery system created with the self-assembling amphiphilic phosphorus dendrons that may be adapted for chemotherapy of different cancer types.
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Antineoplásicos , Neoplasias de la Mama , Dendrímeros , Antineoplásicos/química , Neoplasias de la Mama/tratamiento farmacológico , Dendrímeros/química , Doxorrubicina/química , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Micelas , FósforoRESUMEN
Phosphorus dendrimers are used for many applications in different domains including nanomedicine as cargo of drugs or as species active per se but also in a variety of other fields ranging from nanoscience to catalysis. Their properties depend on the nature of their internal structure and mainly of the diversity and versatility of the functional groups located on their outer shell. Therefore, there is a need to diversify their structure in order to use them for new applications and to propose alternative synthetic pathways to be built easily, at each step and in high yield a family of original stable phosphorus dendrimers of different generations. Such a goal is illustrated in this report with the original synthesis of 14 new phosphorus dendrimers of generation 0 to 2 and the possibility to modify at will their internal structure and the nature of their functional end groups.
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Dendrímeros , Fósforo , Catálisis , Dendrímeros/química , Nanomedicina , Fósforo/químicaRESUMEN
The natural xanthone α-mangostin (αM) exhibits a wide range of pharmacological activities, including antineoplastic and anti-nematode properties, but low water solubility and poor selectivity of the drug prevent its potential clinical use. Therefore, the targeted third-generation poly(amidoamine) dendrimer (PAMAM G3) delivery system was proposed, based on hyperbranched polymer showing good solubility, high biocompatibility and low immunogenicity. A multifunctional nanocarrier was prepared by attaching αM to the surface amine groups of dendrimer via amide bond in the ratio 5 (G32B12gh5M) or 17 (G32B10gh17M) residues per one dendrimer molecule. Twelve or ten remaining amine groups were modified by conjugation with D-glucoheptono-1,4-lactone (gh) to block the amine groups, and two biotin (B) residues as targeting moieties. The biological activity of the obtained conjugates was studied in vitro on glioma U-118 MG and squamous cell carcinoma SCC-15 cancer cells compared to normal fibroblasts (BJ), and in vivo on a model organism Caenorhabditis elegans. Dendrimer vehicle G32B12gh at concentrations up to 20 µM showed no anti-proliferative effect against tested cell lines, with a feeble cytotoxicity of the highest concentration seen only with SCC-15 cells. The attachment of αM to the vehicle significantly increased cytotoxic effect of the drug, even by 4- and 25-fold for G32B12gh5M and G32B10gh17M, respectively. A stronger inhibition of cells viability and influence on other metabolic parameters (proliferation, adhesion, ATP level and Caspase-3/7 activity) was observed for G32B10gh17M than for G32B12gh5M. Both bioconjugates were internalized efficiently into the cells. Similarly, the attachment of αM to the dendrimer vehicle increased its toxicity for C. elegans. Thus, the proposed α-mangostin delivery system allowed the drug to be more effective in the dendrimer-bound as compared to free state against both cultured the cancer cells and model organism, suggesting that this treatment is promising for anticancer as well as anti-nematode chemotherapy.
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Dendrímeros/química , Sistemas de Liberación de Medicamentos , Neoplasias/tratamiento farmacológico , Poliaminas/química , Xantonas/administración & dosificación , Animales , Biotinilación , Caenorhabditis elegans , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Garcinia mangostana , Humanos , Fitoterapia , Xantonas/químicaRESUMEN
Copper nanomaterials based on DNA scaffold (DNA-Cu NMs) are becoming a novel fluorescent material, but it is still challenging to obtain highly fluorescent DNA-Cu NMs with excellent stability. In this work, we report a kind of copper nano-assemblies (Cu NASs) with aggregation-induced emission enhancement (AIEE) property using DNA dendrimers with sticky end as template. The sticky end of the DNA dendrimers induced the formation of much bigger Cu NASs with average size ranging from 131 to 264 nm, depending on the length of the DNA dendrimer sticky end from 6 bases to 27 bases. Compared with complete complementary DNA dendrimer, nearly 6-fold fluorescence enhancement was achieved using DNA dendrimer with 27 bases sticky end. Moreover, the DNA dendrimer-Cu NASs demonstrated excellent stability in serum and could be rapidly quenched by Pb2+ ions. Based on the above property, highly sensitive and selective fluorescent detection of Pb2+ ions was possible with a linear range of 2.0-100 nM and a detection limit of 0.75 nM. Due to the sensitive and rapid response to Pb2+ as well as excellent stability in complex matrix, the proposed fluorescent Cu NASs demonstrated high potential as an excellent fluorescent probe for Pb2+ in complex matrix.
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Cobre/química , ADN/química , Dendrímeros/química , Colorantes Fluorescentes/química , Plomo/análisis , Nanopartículas/química , Fluorescencia , Iones , Plomo/química , Albúmina Sérica Bovina/químicaRESUMEN
Based on phenotypic screening, the major advantages of phosphorus dendrimers and dendrons as drugs allowed the discovery of new therapeutic applications, for instance, as anti-cancer and anti-tuberculosis agents. These biological activities depend on the nature of the chemical groups (neutral or cationic) on their surface as well as their generation. As lessons to learn, in the oncology domain, the increase in the generation of metallo-dendrimers is in the same direction as the anti-proliferative activities, in contrast to the development of polycationic dendrimers, where the most potent anti-tuberculosis phosphorus dendrimer was observed to have the lowest generation (G0). The examples presented in this original analysis of phosphorus dendrimers and dendrons provide support for the lessons learned and for the development of new nanoparticles in nanomedicine.
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Dendrímeros/farmacología , Nanomedicina/tendencias , Fósforo/farmacología , Animales , Antineoplásicos/uso terapéutico , Antituberculosos/uso terapéutico , Dendrímeros/química , Humanos , Estructura Molecular , Nanomedicina/métodos , Nanopartículas/química , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Fósforo/química , Tuberculosis/tratamiento farmacológicoRESUMEN
INTRODUCTION: Pressure ulcer (PU) is known as the third most costly disorder usually caused by prolonged pressure and stagnation in various parts of the body. Although several therapeutic approaches are employing, obstacles in appropriate healing for skin lesions still exist which necessitates new practical alternative or adjunctive treatments. Low level laser therapy (LLLT) as one of the mentioned new strategies have gained attention. Besides, curcumin is an herbal medicine extracted from turmeric with anti-inflammatory and antioxidative properties with promising beneficial therapeutic effects in wound healing. Employing dendrosomal nanoparticles, we overcome the hydrophobicity of curcumin in the present study. We hypothesized that combination treatment of DNC+LLLT (450 nm) simultaneously may promote the wound healing process. MATERIAL AND METHODS: MTT assay, PI staining followed by flowcytometry, scratch assay and intracellular ROS measurement were used to investigate the effects caused by DNC and LLLT (450 nm) alone and in combination, on proliferation, cell cycle, migration and oxidative stress mouse embryonic fibroblast cells, respectively. The levels of growth factors and pro-inflammatory cytokines were evaluated by qRT-PCR and ELISA. RESULTS: Our results indicated that combination exposure with DNC and LLLT leads to increased proliferation and migration of MEFs as well as being more efficient in significantly upregulating growth factors (TGF-ß, VEGF) and decline in inflammatory cytokines (TNF-α, IL-6). Moreover, findings of this research provide persuasive support for the notion that DNC could reduce the LLLT-induced enhancement in intracellular ROS in mouse embryonic fibroblasts. CONCLUSION: Concurrent exposure to anti-oxidant concentrations of DNC and LLLT enriched S phase entry and therefor increased proliferation as well as migration on MEFs through regulating the expression levels growth factors and shortening the inflammatory phase by modulating of cytokines. It should be noted that DNC were able to reduce the laser-induced oxidative stress, during wound healing, representing an informative accompaniment with LLLT.
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Movimiento Celular/efectos de los fármacos , Curcumina/química , Dendrímeros/química , Fibroblastos/efectos de los fármacos , Terapia por Luz de Baja Intensidad , Nanopartículas/química , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Fibroblastos/citología , Fibroblastos/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Interleucina-6/genética , Interleucina-6/metabolismo , Ratones , Factor de Crecimiento Transformador alfa/genética , Factor de Crecimiento Transformador alfa/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Combination treatment through the co-delivery of drugs and genes by nanoformulations may achieve a synergistic effect. In our previous study, poly(amidoamine) dendronized chitosan derivative (PAMAM-Cs) showed good gene transfection efficiency and low cytotoxicity. Here, we incorporated hydrophobic deoxycholic acid (DCA) onto the chitosan backbone of PAMAM-Cs to obtain an amphiphilic derivative-PAMAM-Cs-DCA, which could self-assemble into cationic nanoparticles (NPs). The resulting NPs with diameters of 140-220 nm can encapsulate the hydrophobic anticancer drug doxorubicin (DOX) in the core while bind pDNA via the positively charged PAMAM shell. PAMAM-Cs-DCA NPs could completely complex with pDNA at a ratio of nitrogen to phosphorous (N/P) low as 1 and the complexes achieved a transfection efficiency up to 74 % at N/P 20. Moreover, low-dose co-delivered DOX could enhance the transgene expression, showing a synergistic effect. These results suggest that PAMAM-Cs-DCA NPs hold great promise to co-deliver chemotherapeutics and nucleic acid drugs.
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Quitosano/química , Ácido Desoxicólico/química , Doxorrubicina/administración & dosificación , Vectores Genéticos , Poliaminas/química , Antineoplásicos/farmacología , Cationes , Supervivencia Celular/efectos de los fármacos , Dendrímeros/química , Dendrímeros/farmacología , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Células HEK293 , Humanos , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Técnicas In Vitro , Nanopartículas/química , Nitrógeno/química , Ácidos Nucleicos/química , Tamaño de la Partícula , Fósforo/químicaRESUMEN
The development of functional intelligent theranostic nanoplatform for imaging-directed synchronous inhibition of primary tumor and tumor metastasis is still a challenging task. We present here the creation of functional dendrimer-entrapped CuS nanoparticles (CuS DENPs) complexed with plasmid DNA-encoding hypermethylation in cancer 1 (pDNA-HIC1) for photoacoustic (PA) imaging-directed simultaneous inhibition of tumors and tumor metastasis. Poly(amidoamine) dendrimers of generation 5 were covalently attached with 1,3-propane sultone and arginine-glycine-aspartic acid (RGD) peptide through a spacer of poly(ethylene glycol) and adopted for the templated synthesis of CuS NPs. The prepared functional RGD-CuS DENPs possess a mean CuS core diameter of 4.2 nm, good colloidal stability, and an excellent absorption feature in the second near-infrared window, thus having a photothermal conversion efficiency of 49.8% and an outstanding PA imaging capability. The functional DENPs can effectively deliver pDNA-HIC1 to prevent cancer cell invasion and metastasis in a serum-enhancing manner by virtue of zwitterionic modification-rendered antifouling property. The developed RGD-CuS DENPs/pDNA polyplexes display αvß3 integrin-targeted enhanced anticancer activity through the combined CuS NP-mediated photothermal therapy (PTT) and pDNA delivery-rendered cancer cell metastasis inhibition. This can also be proven by the therapeutic efficacy of a triple-negative breast cancer model in vivo, where inhibition of both the primary subcutaneous tumor and lung metastasis can be realized. The created dendrimer-CuS hybrid nanoplatform represents one of the updated designs of nanomedicine for PA imaging-directed combination PTT/gene therapy of tumors and tumor metastasis.
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Antineoplásicos/farmacología , Incrustaciones Biológicas/prevención & control , Neoplasias de la Mama/tratamiento farmacológico , Cobre/farmacología , Dendrímeros/farmacología , Nanopartículas/química , Técnicas Fotoacústicas , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/diagnóstico por imagen , Cobre/química , Dendrímeros/química , Femenino , Humanos , Neoplasias Mamarias Experimentales/diagnóstico por imagen , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Ratones , Oligopéptidos/química , Oligopéptidos/farmacología , Tamaño de la Partícula , Fototerapia , Polietilenglicoles/química , Polietilenglicoles/farmacología , Propiedades de Superficie , Células Tumorales CultivadasRESUMEN
Dendrimers are hyperbranched macromolecules, which are synthesized step-by-step by the repetition of a series of reactions. While many different types of dendrimers are known, this review focusses on the use of trivalent phosphorus derivatives (essentially phosphines and phosphoramidites) for the synthesis of dendrimers. The first part presents dendrimers constituted of phosphines at each branching point. The other parts display the use of trivalent phosphorus derivatives during the synthesis of dendrimers. Different types of reactions have been applied to phosphines. The very first examples of phosphorus-containing dendrimers were obtained by the alkylation of phosphines. Then, several families of dendrimers were elaborated by reaction of phosphoramidites. Such a type of reaction is the base of the solid phase synthesis of oligonucleotides; it has been applied in particular for the synthesis of dendrimers constituted of oligonucleotides. Finally, the Staudinger reaction between phosphines and azides afforded different families of dendrimers, and was at the origin of accelerated methods of synthesis of dendrimers. Besides, the reactivity of the P=N-P=S linkages created by this reaction led to very original dendritic structures.
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Dendrímeros/química , Fósforo/química , Alquilación , Técnicas de Química Sintética , Dendrímeros/síntesis química , Estructura Molecular , Compuestos Organofosforados/química , Fosfinas/químicaRESUMEN
Nitric oxide (NO) gas nanocarrier materials were prepared via a hierarchical assembly of poly(amido amine) dendrimers with fluorocarbon binding sites (DEN-F) and fluorinated poly(ethylene glycol) (F-PEG) on nitrogen-doped carbon nanohorns (NCNHs). The loading abilities of NO gas in these nanocarrier materials increased with the nitrogen doping of CNH and hierarchies formed by DEN-F and F-PEG. Especially, the ability of CNH-based nanocomposite materials was better than that of graphene-based materials. The loading of NO gas arose an infrared absorption band at 1387 cm-1 and increased the intensity ratio of D and G bands in Raman spectra, although these phenomena diminished after the degas treatment. The antimicrobial effects on bacteria (Escherichia coli and Staphylococcus aureus) increased depending on the loading amount of NO gas. It was confirmed from these results that NO gas weakly interacts with nitrogen-doped CNH and is trapped in the void volumes of DEN-F and F-PEG hierarchies. Thus, the concentric hierarchy is preferable for slow release of NO gas due to the void volumes in DEN-F, F-PEG, and CNH hierarchical organization. This sustained release of NO gas is advantageous with regards to the potential biomedical gas therapy against bacteria and other parasites.
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Antibacterianos/farmacología , Materiales Biocompatibles/farmacología , Dendrímeros/farmacología , Nanocompuestos/química , Óxido Nítrico/farmacología , Polietilenglicoles/farmacología , Antibacterianos/química , Materiales Biocompatibles/química , Carbono/química , Carbono/farmacología , Dendrímeros/química , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Escherichia coli/efectos de los fármacos , Gases , Halogenación , Ensayo de Materiales , Pruebas de Sensibilidad Microbiana , Óxido Nítrico/química , Tamaño de la Partícula , Polietilenglicoles/química , Staphylococcus aureus/efectos de los fármacosRESUMEN
Genome-editing tools such as Cre recombinase (Cre), zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and most recently the clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein system have revolutionized biomedical research, agriculture, microbial engineering, and therapeutic development. Direct delivery of genome editing enzymes, as opposed to their corresponding DNA and mRNA precursors, is advantageous since they do not require transcription and/or translation. In addition, prolonged overexpression is a problem when delivering viral vector or plasmid DNA which is bypassed when delivering whole proteins. This lowers the risk of insertional mutagenesis and makes for relatively easier manufacturing. However, a major limitation of utilizing genome editing proteins in vivo is their low delivery efficiency, and currently the most successful strategy involves using potentially immunogenic viral vectors. This lack of safe and effective non-viral delivery systems is still a big hurdle for the clinical translation of such enzymes. This review discusses the challenges of non-viral delivery strategies of widely used genome editing enzymes, including Cre recombinase, ZFNs and TALENs, CRISPR/Cas9, and Cas12a (Cpf1) in their protein format and highlights recent innovations of non-viral delivery strategies which have the potential to overcome current delivery limitations and advance the clinical translation of genome editing.
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Edición Génica/métodos , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Proteínas Bacterianas/administración & dosificación , Proteínas Asociadas a CRISPR/administración & dosificación , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Dendrímeros/química , Endodesoxirribonucleasas/administración & dosificación , Oro/química , Integrasas/administración & dosificación , Lípidos/química , Nanopartículas/química , Fósforo/química , Polietileneimina/química , Nucleasas de los Efectores Tipo Activadores de la Transcripción/administración & dosificación , Nucleasas con Dedos de Zinc/administración & dosificaciónRESUMEN
Mitochondrial malfunction plays a crucial role in cancer development and progression. Cancer cells show a substantially higher mitochondrial activity and greater mitochondrial transmembrane potential than normal cells. This concept can be exploited for targeting cytotoxic drugs to the mitochondria of cancer cells using mitochondrial-targeting compounds. In this study, a polyamidoamine dendrimer-based mitochondrial delivery system was prepared for curcumin using triphenylphosphonium ligands to improve the anticancer efficacy of the drug in vitro and in vivo. For the in vitro evaluations, various methods, such as viability assay, confocal microscopy, flow cytometry, reactive oxygen species (ROS), and real-time polymerase chain reaction analyses, were applied. Our findings showed that the targeted-dendrimeric curcumin (TDC) could successfully deliver and colocalize the drug to the mitochondria of the cancer cells, and selectively induce a potent apoptosis and cell cycle arrest at G2/M. Moreover, at a low curcumin dose of less than 25 µM, TDC significantly reduced adenosine triphosphate and glutathione, and increased the ROS level of the isolated rat hepatocyte mitochondria. The in vivo studies on the Hepa1-6 tumor-bearing mice also indicated a significant tumor suppression effect and the highest median survival days (Kaplan-Meier survival estimation and log-rank test) after treatment with the TDC construct compared to the free curcumin and untargeted construct. Besides its targeted nature and safety, the expected improved solubility and stability represent the prepared targeted-dendrimeric construct as an up-and-coming candidate for cancer treatment. The results of this study emphasize the promising route of mitochondrial targeting as a practical approach for cancer therapy, which can be achieved by optimizing the delivery method.
Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Curcumina/administración & dosificación , Portadores de Fármacos/química , Neoplasias Hepáticas/tratamiento farmacológico , Poliaminas/química , Animales , Carcinoma Hepatocelular/patología , Fraccionamiento Celular , Línea Celular Tumoral , Curcumina/química , Dendrímeros/química , Estabilidad de Medicamentos , Hepatocitos , Humanos , Neoplasias Hepáticas/patología , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Cultivo Primario de Células , Ratas , Solubilidad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: We present a multimodal nanoplatforms for the treatment of hepatocellular carcinoma (HCC) in vitro. The nanoplatforms are based on polydopamine (PDA)-coated magnetite nanoparticles (NPs) and spheres (sMAG) with PAMAM dendrimers and functionalized with NHS-PEG-Mal (N-hydroxysuccinimide-polyethylene glycol-maleimide) linker, which allows their functionalization with a folic acid derivative. The nanomaterials bearing a folic acid-targeting moiety show high efficiency in killing cancer cells in the dual chemo- and photothermal therapy (CT-PTT) of the liver cancer cells in comparison to modalities performed separately. MATERIALS AND METHODS: All materials are characterized in detail with transmission electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, zeta potential and magnetic measurements. Also, photothermal properties were determined under irradiation of nanoparticles with laser beam of 2 W/cm2. The nontoxicity of nanoparticles with doxorubicin and without was checked by WST and LIVE/DEAD assay. Those tests were also used to evaluate materials bearing folic acid and anticancer drug in combined chemo- and photothermal therapy of HCC. Further, the generation of reactive oxygen species profile was also evaluated using flow cytometry test. RESULTS: Both NPs and sMAG showed high photothermal properties. Nevertheless, the higher photothermal response was found for magnetic spheres. Materials of concentration above 10 µg/mL reveal that their activity was comparable to free doxorubicin. It is worth highlighting that a functionalized magnetic sphere with DOXO more strongly affected the HepG2 cells than smaller functionalized nanoparticles with DOXO in the performed chemotherapy. This can be attributed to the larger size of particles and a different method of drug distribution. In the further stage, both materials were assessed in combined chemo- and photothermal therapy (CT-PTT) which revealed that magnetic spheres were also more effective in this modality than smaller nanoparticles. CONCLUSION: Here, we present two types of nanomaterials (nanoparticles and spheres) based on polydopamine and PAMAM dendrimers g.5.0 functionalized with NHS-PEG-Mal linker terminated with folic acid for in vitro hepatocellular carcinoma treatment. The obtained materials can serve as efficient agents for dual chemo- and photothermal therapy of HCC. We also proved that PDA-coated magnetic spheres were more efficient in therapies based on near-infrared irradiation because determined cell viabilities for those materials are lower than for the same concentrations of nanomaterials based on small magnetic nanoparticles.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Carcinoma Hepatocelular/terapia , Portadores de Fármacos/química , Neoplasias Hepáticas/terapia , Nanopartículas de Magnetita/química , Fototerapia , Animales , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Terapia Combinada , Dendrímeros/química , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Liberación de Fármacos , Humanos , Indoles/química , Neoplasias Hepáticas/tratamiento farmacológico , Polietilenglicoles/química , Polímeros/químicaRESUMEN
Acceleration and unification of drug discovery is important to reduce the effort and cost of new drug development. Diverse chemical and biological conditions, specialized infrastructure and incompatibility between existing analytical methods with high-throughput, nanoliter scale chemistry make the whole drug discovery process lengthy and expensive. Here, we demonstrate a chemBIOS platform combining on-chip chemical synthesis, characterization and biological screening. We developed a dendrimer-based surface patterning that enables the generation of high-density nanodroplet arrays for both organic and aqueous liquids. Each droplet (among > 50,000 droplets per plate) functions as an individual, spatially separated nanovessel, that can be used for solution-based synthesis or analytical assays. An additional indium-tin oxide coating enables ultra-fast on-chip detection down to the attomole per droplet by matrix-assisted laser desorption/ionization mass spectrometry. The excellent optical properties of the chemBIOS platform allow for on-chip characterization and in-situ reaction monitoring in the ultraviolet, visible (on-chip UV-Vis spectroscopy and optical microscopy) and infrared (on-chip IR spectroscopy) regions. The platform is compatible with various cell-biological screenings, which opens new avenues in the fields of high-throughput synthesis and drug discovery.