RESUMEN

Polyamidoamine (PAMAM) dendrimers have been explored as an alternative to polyethylenimine (PEI) as a gene delivery carrier because of their relatively low cytotoxicity and excellent biocompatibility. The transfection efficiency of PAMAM dendrimers can be improved by the addition of nuclear localization signal (NLS), a positively charged peptide sequence recognized by cargo proteins in the cytoplasm for nuclear transport. However, increased positive charges from NLS can cause damage to the cytoplasmic and mitochondrial membranes and lead to reactive oxygen species (ROS)-induced cytotoxicity. This negative effect of NLS can be negated without a significant reduction in transfection efficiency by adding histidine, an essential amino acid known as a natural antioxidant, to NLS. However, little is known about the exact mechanism by which histidine reduces cytotoxicity of NLS-modified dendrimers. In this study, we selected cystamine core PAMAM dendrimer generation 2 (cPG2) and conjugated it with NLS derived from Merkel cell polyomavirus large T antigen and histidine (n = 0-3) to improve transfection efficiency and reduce cytoxicity. NLS-modified cPG2 derivatives showed similar or higher transfection efficiency than PEI 25 kDa in NIH3T3 and human mesenchymal stem cells (hMSC). The cytotoxicity of NLS-modified cPG2 derivatives was substantially lower than PEI 25 kDa and was further reduced as the number of histidine in NLS increased. To understand the mechanism of cytoprotective effect of histidine-conjugated NLS, we examined ROS scavenging, hydroxyl radical generation and mitochondrial membrane potential as a function of the number of histidine in NLS. As the number of hisidine increased, cPG2 scavenged ROS more effectively as evidenced by the hydroxyl radical antioxidant capacity (HORAC) assay. This was consistent with the reduced intracellular hydroxyl radical concentration measured by 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) assay in NIH3T3. Finally, fluorescence imaging with JC-1 confirmed that the mitochondrial membranes of NIH 3T3 were well-protected during the transfection when NLS contained histidine. These experimental results confirm the hypothesis that histidine residues scavenge ROS that is generated during the transfection process, preventing the excessive damage to mitochondrial membranes, leading to reduced cytotoxicity.

Asunto(s)

Dendrímeros , Señales de Localización Nuclear , Animales , Ratones , Humanos , Señales de Localización Nuclear/química , Señales de Localización Nuclear/genética , Señales de Localización Nuclear/metabolismo , Histidina , Dendrímeros/química , Células 3T3 NIH , Antioxidantes/farmacología , Radical Hidroxilo , Especies Reactivas de Oxígeno , ADN/química , Técnicas de Transferencia de Gen , Transfección , Supervivencia Celular

RESUMEN

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.

Asunto(s)

Berberina , Dendrímeros , Humanos , Dendrímeros/química , Portadores de Fármacos/química , Polietilenglicoles/química

RESUMEN

Pesticides are used in the agricultural production process to ensure the yield and quality of agricultural products. However, in recent years, environmental pollution issues caused by pesticide residues have sparked widespread concern in society. It is important to develop convenient and efficient approaches to detect and monitor pesticide residues. In this study, targeting benzoylurea insecticides (BUs), polyamidoamine dendrimer-functionalized silica nanocomposite with polydopamine coating (SiO2-PAMAM-PDA) was designed and successfully synthesized. First, monodisperse silica nanoparticles were prepared by the hydrolysis of tetraethyl orthosilicate (TEOS) in mixed solution of ethanol, water and ammonia. The silane coupling agent (3-aminopropyl)triethoxysilane was then employed to introduce amino groups into the silica. Silica with the zeroth generation of polyamidoamine (PAMAM) modification (SiO2-PAMAM-G0) was obtained through Michael addition reaction of methyl acrylate. Ethylenediamine was added to polymerize with methyl acrylate using an amidation reaction to form the first-generation PAMAM (SiO2-PAMAM-G1). Finally, by polymerizing dopamine under alkaline conditions (pH=8.5), the SiO2-PAMAM-G1 was coated with PDA. Thus, the final product named SiO2-PAMAM-PDA was obtained. The composite was characterized using a transmission electron microscope (TEM) and an increase in surface roughness indicated the successful grafting of PDA coating. Dopamine structure contains abundant benzene rings and amino and hydroxyl groups. It could bind with BUs through multiple secondary interactions, such as hydrogen bond and π-π stacking interaction. Therefore, the introduction of PDA could effectively enhance the affinity of the material toward benzoylurea insecticides. The prepared nanocomposites were used as sorbents in a dispersive micro solid-phase extraction approach (D-µ-SPE). The established approach was employed to extract and enrich the BUs in water samples before high-performance liquid chromatography (HPLC) analysis. Diflubenzuron, triflumuron, hexaflumuron, and teflubenzuron were chosen as target analytes. The following was a typical D-µ-SPE procedure. The prepared adsorbents measuring 40 mg were first dispersed in an 8-mL sample solution containing 150 g/L NaCl. The dispersion was assisted by 120-s vortexing to ensure full contact between the SiO2-PAMAM-PDA and the targets. Next, the adsorbents were separated from the liquid phase by 4-min centrifugation (5000 r/min). Thereafter, the adsorbed benzoylureas were eluted using 1 mL acetonitrile as desorption solvent by 120-s vortexing. Separated by centrifugation, the eluate was dried under a mild nitrogen stream. The solid remains were redissolved in 0.1 mL of acetonitrile, filtered by filter membrane (0.22 µm), and then analyzed by HPLC. The experimental conditions in the D-µ-SPE process could have a great impact on the extraction efficiency. Experimental conditions were optimized using a single factor optimization approach to further enhance the extraction recoveries. The optimized conditions included adsorbent amount, extraction time, desorption solvent type, desorption solvent volume, desorption time, and NaCl addition amount. Under the optimal conditions, a linearity range of 10-500 µg/L and limits of detection (LODs, S/N=3) of 1.1-2.1 µg/L were obtained. The extraction recoveries and relative standard deviations (RSDs) of the four BUs were 82.8%-94.1% and 2.1%-8.0%, respectively. The established approach was compared with reported approaches targeting benzoylurea insecticides. It was discovered that this approach consumed less sample, material, organic solvent, and pretreatment time. It provided a more rapid and green choice for the determination of benzoylurea pesticides. To determine the applicability, the proposed approach was applied to analyze the four benzoylurea insecticides in three river water samples. The real water samples were pretreated using the developed approach ahead of instrumental analysis, and no benzoylurea pesticides residue was detected. Next, standard addition experiments were performed under three spiking levels, including 15, 50, and 200 µg/L. The established approach had good accuracy and feasibility with satisfactory recoveries (69.5%-99.4%) and RSDs (0.2%-9.5%).

Asunto(s)

Dendrímeros , Diflubenzurón , Insecticidas , Nanocompuestos , Residuos de Plaguicidas , Acetonitrilos/análisis , Acrilatos , Amoníaco/análisis , Benceno/análisis , Cromatografía Líquida de Alta Presión , Dendrímeros/análisis , Diflubenzurón/análisis , Dopamina/análisis , Etanol/análisis , Etilenodiaminas/análisis , Indoles , Insecticidas/análisis , Nanocompuestos/análisis , Nitrógeno/análisis , Residuos de Plaguicidas/análisis , Poliaminas , Polímeros , Silanos/análisis , Dióxido de Silicio/análisis , Cloruro de Sodio/análisis , Extracción en Fase Sólida , Solventes/análisis , Agua/análisis

RESUMEN

The aim of this study was to develop a polyethylene glycol (PEG)-conjugated third-generation polyamidoamine dendrimer (PAMAM) with phosphorylated serine as an osteoid surface-targeting drug carrier for the treatment of bone diseases. We conjugated PAMAM backbones to l-serine and obtained Ser-PAMAM. Then, phosphoric acid and PEG were covalently bound to the Ser-PAMAM to generate PEGylated phosphorylated Ser-PAMAM (PEG-phosSer-PAMAM). Using osteoblast-like cells (MC3T3-E1 cells) cultured in 3D collagen gels, we showed that phosSer-PAMAM adsorbed both the hydroxyapatite and type I collagen components of the bone matrix. Fourier transform infrared spectroscopy analysis indicated that the phosphoryl side chains of phosSer-PAMAM formed electrostatic interactions and hydrogen bonds with the anionic amino acid residues of type I collagen. Mice were intravenously injected with the foregoing molecules, and a tissue distribution study disclosed that the lower limb bone took up about twice as much 111In-labeled PEG-phosSer-PAMAM as 111In-labeled nonphosphorylated PEG-Ser-PAMAM or unmodified PAMAM. An intrabone distribution experiment showed that fluorescein isothiocyanate (FITC)-labeled PEG-phosSer-PAMAM accumulated on the osteoid surfaces, which is associated with bone pathogenesis such as skeletal dysplasias and osteoporosis to a far greater extent than nonphosphorylated PEG-Ser-PAMAM. Our findings indicated that PEG-phosSer-PAMAM is a promising carrier for efficient drug targeting to osteoid surfaces.

Asunto(s)

Dendrímeros , Portadores de Fármacos , Animales , Matriz Ósea , Colágeno Tipo I , Dendrímeros/química , Portadores de Fármacos/química , Ratones , Poliaminas , Polietilenglicoles/química , Serina

RESUMEN

BACKGROUND: This study sought to examine the suppression of the NK4 (which is a fragment that originates from the trypsin digestion of the hepatocyte growth factor) gene as mediated by new nano material polyamidoamine (PAMAM) dendrimers in the growth of breast cancer cells MDA-MB-231 and MCF-7, and the therapeutic effects in a nude mice model of transplanted tumor cell MDA-MB-231. METHODS: We built PAMAM-NK4 nano particles and detected the in vitro transfection rate. Nano complexes and blank plasmid PAMAM dendrimers were transfected to MDA-MB-231 and MCF-7 cells, respectively. The western-blotting method, MTT experiment method, and bead method were used to detect the effects of the nano complexes on NK4 protein expression, cell proliferation, and cell apoptosis. The nude mice model of transplanted tumor cell MDA-MB-231 comprised 40 nude female mice who were subject to injections. The mice were randomly divided into four groups, comprising 10 mice per group. The control, blank plasmid and treatment groups were subcutaneously injected with 0.2 mL of 0.9% NaCl (Sodium chloride) solution, 0.2 mL of plasmid solution (including 100 µg PAMAM pcDNA3.1(-) blank plasmid nano complexes) and 0.2 mL of plasmid solution (including PAMAM-NK4 100 µg) beside the tumor inoculation spot, respectively. The positive control group was intraperitoneally injected with 0.2 mL of doxorubicin solution, including 100 µg doxorubicin. Western blotting was used to detect the NK4 protein expression of the transplanted tumor tissues of the various groups. RESULTS: NK4 protein was successfully expressed in MDA-MB-231 and MCF-7 cells transfected with PAMAM-NK4 nano particles, and cell proliferation was suppressed and cell apoptosis was induced. The tumor volumes and masses of the treatment and positive control groups were obviously smaller than those of the control group. The differences were statistically significant (P<0.05). The treatment group had an obviously higher mean value of NK4 protein expression than the control group. The differences were statistically significant (P<0.05). CONCLUSIONS: PAMAM-NK4 nano complexes suppress the growth of the breast cancer cells MDA-MB-231 and MCF-7, and had a treatment effect on this tumor nude mice model of breast cancer cells.

RESUMEN

It is often challenging to design diagnostic and therapeutic agents that fulfill all functional requirements. So, bulk and surface modifications as a common approach for biomedical applications have been suggested. There have been considerable research interests in using nanomaterials to the prementioned methods. Among all nanomaterials, dendritic materials with three-dimensional structures, host-guest properties, and nano-polymeric dimensions have received considerable attention. Amine-terminated dendritic structures including, polyamidoamine (PAMAM), polypropyleneimine (PPI), and polyethyleneimine (PEI), have been enormously utilized in bio-modification. This review briefly described the structure of these three common dendritic polymers and their use to modify diagnostic and therapeutic agents in six major applications, including drug delivery, gene delivery, biosensor, bioimaging, tissue engineering, and antimicrobial activity. The current review covers amine-terminated dendritic polymers toxicity challenging and improvement strategies as well.

Asunto(s)

Aminas/química , Técnicas Biosensibles , Dendrímeros/química , Terapia Genética , Nanoestructuras/química , Polímeros/química , Sistemas de Liberación de Medicamentos , Humanos

RESUMEN

Polyamidoamine (PAMAM) dendrimers are biocompatible polymers utilized in multiple biomedical applications including tissue engineering, medical diagnosis, drug and gene delivery systems, and biosensors. Normally, high-generation PAMAM dendrimers are advantageous for use in gene therapy research because they have a relatively high transfection efficiency. A high-generation PAMAM dendrimer has a high charge density, which induces greater damage to the membranous organelles than that induced by a low-generation PAMAM dendrimer. In this study, we added NLS sequences derived from the human papillomavirus (HPV) type 11 E2 protein to the low-generation PAMAM generation 2 (PAMAM G2) dendrimer and simultaneously introduced histidine residues to reduce cytotoxicity. RKRARH-PAMAM G2 showed similar and high transfection efficiencies in Neuro-2A and NIH3T3 cell lines and relatively low cytotoxicities relative to that of polyethylenimine 25 kDa (PEI 25 kDa).

Asunto(s)

Dendrímeros , Señales de Localización Nuclear , Animales , Supervivencia Celular , Técnicas de Transferencia de Gen , Terapia Genética , Papillomavirus Humano 11 , Humanos , Ratones , Células 3T3 NIH , Poliaminas

RESUMEN

Polyamidoamine (PAMAM) dendrimer is an extensively studied polymer in the biomedical research because of its low polydispersity, distinct molecular structure, and surface functionalities. Generally, a high-generational PAMAM dendrimer is used for gene delivery because transfection efficiency is dependent on charge density; however, an increase in charge density induces disruption of the cellular membrane, and damage to the membrane results in cytotoxicity. In this study, we selected PAMAM generation 2 to reduce the cytotoxic effect and conjugated RRILH and RRLHL sequences, nuclear localization signals (NLS) derived from herpesviridae to PAMAM generation 2. The transfection efficiency of RRILH-PAMAM G2 and RRLHL-PAMAM G2 was similar to that of polyethylenimine (PEI) in Neuro2A, HT22, and HaCaT cells, whereas their transfection efficiency was much higher than that of PEI in NIH3T3 cells. RRILH-PAMAM G2 showed relatively lower cytotoxicity than did RRLHL-PAMAM G2 in all cell lines, but the transfection capacity of the two polymers was similar. Our study shows that low-generational PAMAM dendrimer conjugated with NLS sequences has potential as an alternative to PEI in gene delivery.

Asunto(s)

Dendrímeros , Herpesviridae , Animales , Ratones , Células 3T3 NIH , Señales de Localización Nuclear , Poliaminas , Transfección

RESUMEN

This study investigates the formation of a graphene oxide-polyamidoamine dendrimer complex (GO-PAMAM) and its association and interaction with bovine serum albumin (BSA). Fourier-transform infrared spectrometry and X-ray photoelectron spectrometry indicated the formation of covalent linkage between the GO surface and PAMAM with 7.22% nitrogen content in the GO-PAMAM sample, and various interactions between BSA and GO-PAMAM, including π-π* interactions at 291.5 eV for the binding energy value. Thermogravimetric analysis highlighted the increasing thermal stability throughout the modification process, from 151 to 192 °C for the 10% weight loss temperature. Raman spectrometry and X-ray diffraction analysis were used in order to examine the complexes' assembly, showing a prominent (0 0 2) lattice in GO-PAMAM. Dynamic light scattering tests proved the formation of stable graphenic and graphenic-protein aggregates. The secondary structure rearrangement of BSA after interaction with GO-PAMAM was investigated using circular dichroism spectroscopy. We have observed a shift from 10.9% ß-sheet composition in native BSA to 64.9% ß-sheet composition after the interaction with GO-PAMAM. This interaction promoted the rearrangement of the protein backbone, leading to strongly twisted ß-sheet secondary structure architecture.

RESUMEN

Targeted delivery of chemotherapeutics to tumors has the potential to reach a high dose at the tumor while minimizing systemic exposure. Incorporation of antibody within a micellar platform represents a drug delivery system for tumor-targeted delivery of antitumor agents. Such modified immunomicelles can result in an increased accumulation of antitumor agents and enhanced cytotoxicity toward cancer cells. Here, mixed dendrimer micelles (MDM) composed of PEG2k-DOPE-conjugated generation 4 polyamidoamine dendrimer G4-PAMAM-PEG2k-DOPE and PEG5k-DOPE were coloaded with doxorubicin and siMDR-1. This formulation was further modified with monoclonal antibodies 2C5 with nucleosome-restricted specificity that effectively recognized cancer cells via the cell-surface-bound nucleosomes. Micelles with attached 2C5 antibodies significantly enhanced cellular association and tumor killing in both monolayer and spheroid tumor models as well as in vivo in experimental animals compared to the nontargeted formulations.

Asunto(s)

Anticuerpos Monoclonales/química , Antineoplásicos/administración & dosificación , Dendrímeros/química , Sistemas de Liberación de Medicamentos , Micelas , Neoplasias Experimentales/tratamiento farmacológico , ARN Interferente Pequeño/administración & dosificación , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacocinética , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Composición de Medicamentos , Femenino , Humanos , Ratones , Neoplasias Experimentales/patología , Esferoides Celulares , Distribución Tisular

RESUMEN

BACKGROUND: Polyamidoamine (PAMAM) dendrimers have been investigated for decades and currently applied in various areas throughout nanomedicine, including gene therapy, drug delivery, anti-bacteria and imaging. It is therefore necessary to assess cytotoxicity of PAMAM dendrimers systematically. Because blood component is usually the initial step of contact with any therapeutic agent, comprehensive hemocompatibility study is needed. MATERIAL S AND METHODS: The triblock dendrimer: polyamidoamine-polyethylene glycol-cyclic RGD (PAMAM-PEG-cRGD), was successfully synthesized. Various in vitro assays to characterize hemocompatibility of both PAMAM (Generation 4.0) and PAMAM-PEG-cRGD were performed, including hemolytic assay, platelet activation examination, platelet counting, assessment of coagulating pathways and evaluation of complement system activation. RESULTS: The hemolytic ratio of PAMAM-PEG-cRGD maintained below 5%. Surface engineering of PEG and cRGD to PAMAM attenuated hemolysis and RBC aggregation as compared with unmodified PAMAM. PAMAM (Generation 4.0) reduced platelet counting in a dose-dependent manner, and the platelet number dropped dramatically at a relatively low incubating dose (1 µM). Such surface modifications also alleviated platelet activation and platelet reduction mediated by PAMAM polycationicity. Finally, high concentration (10 µM) of PAMAM interfered the coagulation system, prolonging prothrombin time significantly. CONCLUSION: Surface modification of PEG and cRGD to PAMAM (Generation 4.0) improves hemocompatibility. Introduction of PEG and cRGD significantly mitigates hemolytic and RBC aggregation effects as compared with unmodified PAMAM. Similarly, these modifications alleviate platelet activation and platelet reduction mediated by PAMAM polycationicity.

Asunto(s)

Dendrímeros/metabolismo , Poliaminas/metabolismo , Humanos , Técnicas In Vitro

RESUMEN

Carboplatin (CAR) is a second generation platinum-based compound emerging as one of the most widely used anticancer drugs to treat a variety of tumors. In an attempt to address its dose-limiting toxicity and fast renal clearance, several delivery systems (DDSs) have been developed for CAR. However, unsuitable size range and low loading capacity may limit their potential applications. In this study, PAMAM G3.0 dendrimer was prepared and partially surface modified with methoxypolyethylene glycol (mPEG) for the delivery of CAR. The CAR/PAMAM G3.0@mPEG was successfully obtained with a desirable size range and high entrapment efficiency, improving the limitations of previous CAR-loaded DDSs. Cytocompatibility of PAMAM G3.0@mPEG was also examined, indicating that the system could be safely used. Notably, an in vitro release test and cell viability assays against HeLa, A549, and MCF7 cell lines indicated that CAR/PAMAM G3.0@mPEG could provide a sustained release of CAR while fully retaining its bioactivity to suppress the proliferation of cancer cells. These obtained results provide insights into the potential of PAMAM G3.0@mPEG dendrimer as an efficient delivery system for the delivery of a drug that has strong side effects and fast renal clearance like CAR, which could be a promising approach for cancer treatment.

Asunto(s)

Carboplatino/química , Dendrímeros/química , Portadores de Fármacos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Dendrímeros/toxicidad , Portadores de Fármacos/toxicidad , Liberación de Fármacos , Humanos , Ensayo de Materiales , Polietilenglicoles/química , Propiedades de Superficie

RESUMEN

Polyamidoamine (PAMAM) dendrimers are extensively researched as potential drug delivery system thanks to their desirable features such as controlled and stable structures, and ease of functionalization onto their surface active groups. However, there have been concerns about the toxicity of full generation dendrimers and risks of premature clearance from circulation, along with other physical drawbacks presented in previous formulations, including large particle sizes and low drug loading efficiency. In our study, carboxyl-terminated PAMAM dendrimer G3.5 was grafted with poly (ethylene glycol) methyl ether (mPEG) to be employed as a nano-based drug delivery system with great cytocompatibility for the delivery of carboplatin (CPT), a widely prescribed anticancer drug with strong side effects so that the drug will be effectively entrapped and not exhibit uncontrolled outflow from the open structure of unmodified PAMAM G3.5. The particles formed were spherical in shape and had the optimal size range (around 36 nm) that accommodates high drug entrapment efficiency. Surface charge was also determined to be almost neutral and the system was cytocompatible. In vitro release patterns over 24 h showed a prolonged CPT release compared to free drug, which correlated to the cytotoxicity assay on malignant cell lines showing the lack of anticancer effect of CPT/mPEG-G3.5 compared with CPT.

Asunto(s)

Antineoplásicos/administración & dosificación , Materiales Biocompatibles/química , Carboplatino/administración & dosificación , Dendrímeros/química , Portadores de Fármacos/química , Antineoplásicos/farmacología , Carboplatino/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Humanos , Neoplasias/tratamiento farmacológico , Polietilenglicoles/química

RESUMEN

Preparation of excellent dye adsorbent that simultaneously displays convenient separation capability, high adsorption capacity, fast removal rate, superior adsorption selectivity, and favorable reusability remains a challenge. Herein, we present a simple and feasible one-step method to prepare amine-rich porous polyamidoamine (PAMAM) dendrimer gel adsorbent. The PAMAM gel could be readily separated from water by filtration. The adsorption properties of PAMAM gel was systematically examined by adsorption of anionic methyl orange (MO) and tartrazine (TTZ) dyes. The PAMAM gel exhibited superior adsorption selectivity and removal efficiency towards anionic MO and TTZ dyes. The adsorption process could be completed within around 15 min and presented fine correlation with Langmuir isotherm and pseudo-second-order kinetic models. The maximum adsorption capacity of PAMAM gel towards MO and TTZ was as high as 680.2 mg g-1 and 689.7 mg g-1, respectively. Additionally, the dye-adsorbed PAMAM gel could be readily desorbed in alkaline solution. Considering the simple synthetic process and outstanding adsorption performance of PAMAM gel, this paper provides an effective approach to prepare high-performance anionic dye adsorbents.

RESUMEN

In this work, a novel adsorbent with stabilizing of PAMAM dendrimer on the surface of sand was successfully synthesized and used to remove NP from water. The characterization of the adsorbent was performed by XRD, FTIR, TEM, and FE-SEM. Batch and column studies were conducted to evaluate the performance of the adsorbent. It was found that Freundlich isotherm and pseudo-second order models are perfectly stimulated the adsorption behavior and kinetic rate of NP uptake. In column study, first the effect of bed depth, flow rate and initial concentration of NP on the performance of the adsorbent were evaluated then the breakthrough curve for each condition was drawn. Finally, Thomas model constants to describe NP adsorption were calculated. As the result of the experiments, it might be concluded that in conventional water treatment plants which the removal of NP is negligible, the use of synthesized adsorbent as a filter media can be a promising way to selectively remove NP from water.

RESUMEN

Multidrug resistance (MDR) significantly decreases the therapeutic efficiency of anti-cancer drugs. Its reversal could serve as a potential method to restore the chemotherapeutic efficiency. Downregulation of MDR-related proteins with a small interfering RNA (siRNA) is a promising way to reverse the MDR effect. Additionally, delivery of small molecule therapeutics simultaneously with siRNA can enhance the efficiency of chemotherapy by dual action in MDR cell lines. Here, we conjugated the dendrimer, generation 4 polyamidoamine (G4 PAMAM), with a polyethylene glycol (PEG)-phospholipid copolymer. The amphiphilic conjugates obtained spontaneously self-assembled into a micellar nano-preparation, which can be co-loaded with siRNA onto PAMAM moieties and sparingly water-soluble chemotherapeutics into the lipid hydrophobic core. This system was co-loaded with doxorubicin (DOX) and therapeutic siRNA (siMDR-1) and tested for cytotoxicity against MDR cancer cells: human ovarian carcinoma (A2780 ADR) and breast cancer (MCF7 ADR). The combination nanopreparation effectively downregulated P-gp in MDR cancer cells and reversed the resistance towards DOX.

Asunto(s)

Dendrímeros/administración & dosificación , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Nanomedicina/métodos , Poliaminas/administración & dosificación , ARN Interferente Pequeño/administración & dosificación , Dendrímeros/metabolismo , Resistencia a Múltiples Medicamentos/fisiología , Resistencia a Antineoplásicos/fisiología , Quimioterapia Combinada , Humanos , Células MCF-7 , Nanomedicina/tendencias , Poliaminas/metabolismo , ARN Interferente Pequeño/metabolismo

RESUMEN

The CD44 protein, as a predominant receptor for hyaluronan (HA), is highly expressed on the surface of multiple tumor cells. HA, as a targeting molecule for a CD44-contained delivery system, increases intracellular drug concentration in tumor tissue. However, due to the weak binding ability of hyaluronan oligosaccharide to CD44, targeting for tumor drug delivery has been restricted. In this study, we first use a HA tetrasaccharide cluster as the target ligand to enhance the binding ability to CD44. A polyamidoamine (PAMAM) dendrimer was modified by a HA tetrasaccharide cluster as a nonviral vector for small interfering RNA (siRNA) delivery. The dendrimer/siRNA nanocomplexes increased the cellular uptake capacity of siRNA through the CD44 receptor-mediated endocytosis pathway, allowing the siRNA to successfully escape the endosome/lysosome. Compared with the control group, nanocomplexes effectively reduced the expression of GFP protein and mRNA in MDA-MB-231-GFP cells. This delivery system provides a foundation to increase the clinical applications of PAMAM nanomaterials.

RESUMEN

AIM: To develop a nanocarrier for targeted delivery of agents to the cartilage. MATERIALS & METHODS: Chondrocyte affinity peptide modified PEGylated polyamidoamine conjugates (CAP-PEG-PAMAM) were prepared and rhodamine B isothiocyanate (RB) fluorophore was linked on them for comparative biological tracing and profiling. RESULTS: CAP4-PP-RB exhibited much more efficient cellular uptake in vitro than that of PEG-PAMAM-RB. Both the conjugates were likely internalized by chondrocytes via clathrin and caveolin co-mediated endocytosis, and delivered to lysosomes. In vivo imaging demonstrated the fluorescein-labeled nanocarrier was capable to persist in the joint cavity of rats for a prolonged time. Furthermore, the CAP4-PEG-PAMAM showed a good biocompatibility and enhanced penetration effects in vivo. CONCLUSION: CAP-PEG-PAMAM could be an effective nanocarrier for intra-articular delivery of agents to cartilage.

Asunto(s)

Dendrímeros/administración & dosificación , Portadores de Fármacos/administración & dosificación , Articulaciones/efectos de los fármacos , Nanopartículas/administración & dosificación , Péptidos/administración & dosificación , Polietilenglicoles/administración & dosificación , Animales , Materiales Biocompatibles/administración & dosificación , Materiales Biocompatibles/química , Cartílago/efectos de los fármacos , Caveolina 1/química , Condrocitos/efectos de los fármacos , Clatrina/química , Dendrímeros/química , Portadores de Fármacos/química , Endocitosis/efectos de los fármacos , Humanos , Articulaciones/patología , Lisosomas/efectos de los fármacos , Masculino , Nanopartículas/química , Péptidos/química , Polietilenglicoles/química , Ratas , Rodaminas/administración & dosificación , Rodaminas/química

RESUMEN

In this study, we aimed to develop a polyethylene glycol (PEG)-conjugated third generation polyamidoamine (PAMAM) dendrimer with multiple carboxylic acids as a bone-targeting carrier for the treatment of bone diseases. We conjugated PAMAM backbones to various carboxylic acids [aspartic acid (Asp), glutamic acid (Glu), succinic acid (Suc), or aconitic acid (Aco)] to obtain four different types of carboxylic acid-modified PAMAMs. PEG was covalently bound to carboxylic acid-modified PAMAMs to obtain PEGylated carboxylic acid-modified PAMAMs. In a tissue distribution study, the amount of 111In-labeled unmodified PAMAM taken up by the bone after intravenous injection in mice was 11.3%. In contrast, the dose of 111In-labeled PEG(5)-Asp-PAMAM, PEG(5)-Glu-PAMAM, PEG(5)-Suc-PAMAM, or PEG(5)-Aco-PAMAM that accumulated in the bone after injection was approximately 46.0, 15.6, 22.6, and 24.5%, respectively. The bone clearance rates of 111In-labeled PEGylated carboxylic acid-modified PAMAMs were proportional to their affinities to hydroxyapatite and Ca2+. An intra-bone distribution study showed that fluorescein isothiocyanate-labeled PEG(5)-Asp-PAMAM predominantly accumulated on eroded and quiescent surfaces, a pattern associated with the pathogenesis of bone diseases, such as rheumatoid arthritis and osteoporosis. Our findings indicate that PEG(5)-Asp-PAMAM is a promising drug carrier for efficient drug targeting to the bones.

Asunto(s)

Huesos/metabolismo , Ácidos Carboxílicos/administración & dosificación , Dendrímeros/administración & dosificación , Portadores de Fármacos/administración & dosificación , Polietilenglicoles/administración & dosificación , Animales , Enfermedades Óseas/tratamiento farmacológico , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/uso terapéutico , Dendrímeros/química , Dendrímeros/farmacocinética , Dendrímeros/uso terapéutico , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/uso terapéutico , Masculino , Ratones , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Polietilenglicoles/uso terapéutico

RESUMEN

Capecitabine, an effective anticancer drug in colorectal cancer chemotherapy, may create adverse side effects on healthy tissues. In the present study, we first induced colon adenocarcinoma with azoxymethane, a carcinogen agent, and then investigated the potentiality of polyamidoamine (PAMAM) dendrimer to improve capecitabine therapeutic index and decrease its adverse side effects on healthy tissues like liver and bone marrow. Other variables such as nanoparticle concentrations have also been investigated. Drug loading concentration (DLC) and encapsulation efficiency (EE) were calculated for capecitabine/dendrimer complex. Experimental results showed an increase in DLC percentage resulted from elevated capecitabine/dendrimer ratio. Capecitabine/dendrimer complex could reduce tumor size and adverse side effects in comparison with free capecitabine form.

Asunto(s)

Capecitabina/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Dendrímeros/administración & dosificación , Modelos Animales , Terapia Molecular Dirigida , Nanopartículas , Poliaminas/administración & dosificación , Animales , Terapia Genética , Ratones , Ratones Endogámicos