Ultrasound-Triggered Microbubbles: Novel Targeted Core-Shell for the Treatment of Myocardial Infarction Disease.

Myocardial infarction (MI) is known as a main cardiovascular disease that leads to extensive cell death by destroying vasculature in the affected cardiac muscle. The development of ultrasound-mediated microbubble destruction has inspired extensive interest in myocardial infarction therapeutics, targeted delivery of drugs, and biomedical imaging. In this work, we describe a novel therapeutic ultrasound system for the targeted delivery of biocompatible microstructures containing basic fibroblast growth factor (bFGF) to the MI region. The microspheres were fabricated using poly(lactic-co-glycolic acid)-heparin-polyethylene glycol- cyclic arginine-glycine-aspartate-platelet (PLGA-HP-PEG-cRGD-platelet). The micrometer-sized core-shell particles consisting of a perfluorohexane (PFH)-core and a PLGA-HP-PEG-cRGD-platelet-shell were prepared using microfluidics. These particles responded adequately to ultrasound irradiation by triggering the vaporization and phase transition of PFH from liquid to gas in order to achieve microbubbles. Ultrasound imaging, encapsulation efficiency cytotoxicity, and cellular uptake of bFGF-MSs were evaluated using human umbilical vein endothelial cells (HUVECs) in vitro. In vivo imaging demonstrated effective accumulation of platelet- microspheres injected into the ischemic myocardium region. The results revealed the potential use of bFGF-loaded microbubbles as a noninvasive and effective carrier for MI therapy.

Development of a graphene oxide-poly lactide nanocomposite as a Smart Drug Delivery System.

In this study, a nanoscale graphene oxide polymer composite drug delivery system was synthesized and investigated for possible oral delivery of doxorubicin. A doxorubicin-loaded nanocomposite composed of graphene oxide/poly(2-hydroxyethylmethacrylate)-g-poly(lactide)-b-polyethyleneglycol-b-poly(2-hydroxyethylmethacrylate)-g-poly(lactide) GO/(PHEMA-g-PLA)-b-PEG-b-(PHEMA-g-PLA) was synthesized via reversible addition fragmentation chain (RAFT) and ring open polymerization (ROP). The GO/(PHEMA-g-PLA)-b-PEG-b- (PHEMA-g-PLA) nanocomposites was characterized by scanning electron microscopy (FE-SEM), thermogravimetry (TG), ultraviolet-visible (UV-Vis) spectroscopy, and dynamic light scattering (DLS). Doxorubicin was successfully loaded into the nanocomposite with a small particle size of 51 nm and an encapsulation efficiency (EE) of 82% ±1.12%. The results showed that DOX was attached to the graphene surface via hydrophobic interactions and π-π stacking. DOX release took place under neutral and acidic conditions, reaching 24.7% and 41.2% respectively after 72 h. Cytotoxicity experiments on 4T1 murine breast cancer cells demonstrated the antitumor activity of the DOX@GO nanocomposite. Biocompatibility, cell uptake, DAPI staining, Annexin V/PI double staining, intracellular reactive oxygen species (ROS) assay, and scratch healing assay were measured. The DOX@graphene nanocomposite system could be promising for breast cancer therapy.

Polystyrene Magnetic Nanocomposites as Antibiotic Adsorbents.

There are different ways for antibiotics to enter the aquatic environment, with wastewater treatment plants (WWTP) considered to be one of the main points of entrance. Even treated wastewater effluent can contain antibiotics, since WWTP cannot eliminate the presence of antibiotics. Therefore, adsorption can be a sustainable option, compared to other tertiary treatments. In this direction, a versatile synthesis of poly(styrene-block-acrylic acid) diblock copolymer/Fe3O4 magnetic nanocomposite (abbreviated as P(St-b-AAc)/Fe3O4)) was achieved for environmental applications, and particularly for the removal of antibiotic compounds. For this reason, the synthesis of the P(St-b-AAc) diblock copolymer was conducted with a reversible addition fragmentation transfer (RAFT) method. Monodisperse superparamagnetic nanocomposite with carboxylic acid groups of acrylic acid was adsorbed on the surface of Fe3O4 nanoparticles. The nanocomposites were characterized with scanning electron microscopy (SEM), X-ray diffraction (XRD) and vibrating sample magnetometer (VSM) analysis. Then, the nanoparticles were applied to remove ciprofloxacin (antibiotic drug compound) from aqueous solutions. The effects of various parameters, such as initial drug concentration, solution pH, adsorbent dosage, and contact time on the process were extensively studied. Operational parameters and their efficacy in the removal of Ciprofloxacin were studied. Kinetic and adsorption isothermal studies were also carried out. The maximum removal efficiency of ciprofloxacin (97.5%) was found at an initial concentration of 5 mg/L, pH 7, adsorbent's dosage 2 mg/L, contact time equal to 37.5 min. The initial concentration of antibiotic and the dose of the adsorbent presented the highest impact on efficiency. The adsorption of ciprofloxacin was better fitted to Langmuir isotherm (R2 = 0.9995), while the kinetics were better fitted to second-order kinetic equation (R2 = 0.9973).

Chrysin and Docetaxel Loaded Biodegradable Micelle for Combination Chemotherapy of Cancer Stem Cell.

PURPOSE: Cancer stem cells (CSCs) have been suggested to represent the main cause of tumour progression, metastasis and drug resistance. Therefore, these cells can be an appropriate target to improve cancer treatment. METHODS: A novel biodegradable brush copolymeric micelle was synthesized by the ring-opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. The obtained micelle was used for co-delivery of the anticancer drug docetaxel (DTX) and Chrysin (CHS) as an adjuvant on the CSCs originated from Human colon adenocarcinoma cell line. Cancer stem cells were enriched by MACS technique and characterized by flow cytometry analysis against CD133 marker. RESULTS: Data demonstrated that the micelles harbouring DTX@CHS had potential to reduce cancer stem cell viability compared to free DTX@CHS, single-drug formulations and the control group (p < 0.05). The combination effect of DTX and CHS formulated in micelle was synergistic in CSCs (CI < 1). The reactive oxygen species content was shown to increase after cell treatment with DTX@CHS loaded on micelles (p < 0.05). DTX@CHS-micelles inhibited cancer stem cell migration rate in vitro (p < 0.05), indicating an impaired metastasis activity. CONCLUSION: In conclusion, the synthesized DOX@CHS-micelles can be applied in the introduction of anticancer agents to resistant cancer population by further investigations.

A perfect stimuli-responsive magnetic nanocomposite for intracellular delivery of doxorubicin.

Iron oxide nanoparticles (IONs) have been extensively applied in cancer therapy and theranostics due to their admissible magnetic properties, excellent chemical stability and biocompatibility. Herein, a novel stimuli-responsive magnetic nanocomposite was synthesized for cancer therapy; thereby, the triblock copolymer of poly[(2-succinyloxyethylmethacrylate)-b-(N-isopropylacrylamide)-b-dimethylaminoethylmethacrylate) [poly(SEMA-b-NIPAM-b-DMAEMA)] was prepared by reversible addition of fragmentation chain transfer (RAFT) polymerization. This triblock copolymer with carboxylic groups of succinyloxyethylmethacrylate was adsorbed onto the surface of Fe3O4 nanoparticles. The morphology, nanocomposite properties and stimuli-responsive behaviours were investigated by field emission scanning electron microscopy, X-ray diffraction, dynamic light scattering, vibrating sample magnetometer (VSM) and thermogravimetric analysis. Doxorubicin (DOX) encapsulation efficacy was 94.3%. Release behaviours of DOX from the magnetic nanocomposite exhibited that the rate of DOX release could be efficiently controlled through temperature and pH. The cytotoxicity of the drug was investigated in vitro against breast cancer cell line (MCF7) using (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assays, 4',6-diamidino-2-phenylindole (DAPI) staining and cellular uptake. In conclusion, the synthesized DOX@nanocomposite can be applied in theranostic applications and anticancer drug delivery owing to admissible properties.

Synthesis and characterization of novel P(HEMA-LA-MADQUAT) micelles for co-delivery of methotrexate and Chrysin in combination cancer chemotherapy.

A Novel poly [2-hydroxyethyl methacrylate-Lactide-dimethylaminoethyl methacrylate quaternary ammonium alkyl halide] [P(HEMA-LA-MADQUAT)] copolymer was synthesized through combination of ring opening polymerization (ROP) and 'free' radical initiated polymerization methods. This newly developed copolymer was fully characterized by FT-IR, 1HNMR and 13CNMR spectroscopy. Micellization of the copolymer was performed by dialysis membrane method and obtained micelles were characterized by FESEM, dynamic light scattering (DLS), zeta potential (ξ), and critical micelle concentration (CMC) measurements. This copolymer was developed with the aim of co-delivering two different anticancer drugs: methotrexate (MTX) and chrysin. In vitro cytotoxicity effect of MTX@Chrysin-loaded P(HEMA-LA-MADQUAT) was also studied through assessing the survival rate of breast cancer cell line (MCF-7) and DAPI staining assays. Cationic micelle (and surface charge of + 7.6) with spherical morphology and an average diameter of 55 nm and CMC of 0.023 gL-1 was successfully obtained. Micelles showed the drug loaded capacity around 87.6 and 86.5% for MTX and Chrysin, respectively. The cytotoxicity assay of a drug-free nanocarrier on MCF-7 cell lines indicated that this developed micelles were suitable nanocarriers for anticancer drugs. Furthermore, the MTX@Chrysin-loaded micelle had more efficient anticancer performance than free dual anticancer drugs (MTX @ chrysin), confirmed by MTT assay and DAPI stainingmethods. Therefore, we envision that this recently developed novel micelle can enhance the efficacy of chemotherapeutic agents, MTX and Chrysin, combination chemotherapy and has the potential to be used as an anticancer drug delivery system for in vivo studies. Therefore, this recently developed novel micelle can enhance the efficacy of chemotherapeutic agents, MTX and Chrysin, combination chemotherapy and has the potential to be used as an anticancer drug delivery system for in vivo studies.

A new style for synthesis of thermo-responsive Fe3O4/poly (methylmethacrylate-b-N-isopropylacrylamide-b-acrylic acid) magnetic composite nanosphere and theranostic applications.

In this work, a novel thermo-responsive Fe3O4/poly(methylmethacrylate-b-N-isopropylacrylamide-b-acrylic acid) magnetic composite nanosphere was synthesized for anticancer drug delivery applications. For this propose, the poly(methylmethacrylate-b-N-isopropylacrylamide-b-acrylic acid) [poly (MMA-b-NIPAAm-b-AAc)] was synthesized via reversible addition-fragmentation transfer method. The physic-chemical characterization of the Fe3O4/poly(MMA-b-NIPAAm-b-AAc) magnetic composite nanosphere was investigated by FTIR, HNMR spectroscopies and GPC, FESEM, XRD, VSM and DLS. The thermo-sensitivity of the Fe3O4/P(MMA-b-NIPAAm-b-AAc) magnetic composite nanosphere was confirmed via DLS at 40 °C. DOX encapsulation efficiency was calculated to be 98.2%. The effect of temperature and pH on release behaviors of stimuli responsive DOX-loaded Fe3O4/P(MMA-b-NIPAAm-b-AAc)] magnetic composite nanosphere were investigated. The release rate at pH 7.4, 5.4 and 4 (T = 37 °C) was reached about 24.4, 42.4 and 57.5 wt%, after 4-5 day. The release rate improved at tumor simulated environment (t:40 °C and pH ≤ 5.4). The cytotoxic effects of the magnetic composite nanosphere were appraised by MTT assay and the results indicated that novel developed smart nanocomposite here was nontoxic to MCF-7 cells and can be applied as anti-cancer drug delivery system. Also, the results of the Cellular uptake of MCF7 cells treated with rhodamine labeled DOX-loaded nanocarrier for 2 h have indicated that DOX can be applied as cytotoxic agent and targeting ligand.

Novel 'schizophrenic' diblock copolymer synthesized via RAFT polymerization: poly(2-succinyloxyethyl methacrylate)-b-poly[(N-4-vinylbenzyl),N,N-diethylamine].

This article describes the synthesis and characterization of a novel 'schizophrenic' diblock copolymer [poly(2-succinyloxyethyl methacrylate)-b-poly[(N-4-vinylbenzyl),N,N-diethylamine)]; PSEMA-b-PVEA] via reversible addition of fragmentation chain transfer (RAFT) polymerization technique. The chemical structures of all samples as representatives were characterized by means of Fourier transform infrared (FTIR), and 1H nuclear magnetic resonance (NMR) spectroscopies. The molecular weights of PHEMA and PVEA segments were calculated to be 9770 and 12,630 gmol-1, respectively, from 1H NMR spectroscopy. The self-assembly behavior of the synthesized PSEMA-b-PVEA diblock copolymer was investigated by means of 1H NMR spectroscopy, dynamic light scattering (DLS) measurements, and transmission electron microscopy (TEM) observation. The average sizes of the PSEMA-b-PVEA micelles at pHs 3.0, 6.0, and 10.0 were obtained to be 294, 237, and 201 nm, respectively, from DLS analysis. The zeta potential measurements at various pHs demonstrated that the synthesized PSEMA-b-PVEA diblock copolymer has zwitterionic properties, and the range of isoelectric point's (IEP's) was determined as 5.8-7.3. It is expected that the synthesized PSEMA-b-PVEA diblock copolymer considered as a prospective candidate in nanomedicine applications such as drug delivery, mainly due to its excellent 'schizophrenic' micellization behavior.

Novel dual stimuli-responsive ABC triblock copolymer: RAFT synthesis, "schizophrenic" micellization, and its performance as an anticancer drug delivery nanosystem.

A novel pH- and thermo-responsive ABC triblock copolymer {poly[(2-succinyloxyethyl methacrylate)-b-(N-isopropylacrylamide)-b-[(N-4-vinylbenzyl),N,N-diethylamine]]} [P(SEMA-b-NIPAAm-b-VEA)] was successfully synthesized via reversible addition of fragmentation chain transfer (RAFT) polymerization technique. The molecular weights of PHEMA, PNIPAAm, and PVEA segments in the synthesized triblock copolymer were calculated to be 10,670, 6140, and 9060gmol-1, respectively, from proton nuclear magnetic resonance (1H NMR) spectroscopy. The "schizophrenic" self-assembly behavior of the synthesized P(SEMA-b-NIPAAm-b-VEA) triblock copolymer under pH and thermal stimulus were investigated by means of 1H NMR and ultraviolet-visible (UV-vis) spectroscopies as well as dynamic light scattering (DLS) and zeta potential (ξ) measurements. The doxorubicin hydrochloride (DOX)-loading capacity, and stimuli-responsive drug release ability of the synthesized triblock copolymer were also investigated. The biocompatibility of the synthesized triblock copolymer was confirmed through the assessing survival rate of breast cancer cell line (MCF7) using MTT assay. In contrast, DOX-loaded triblock copolymer exhibited an efficient anticancer performance in comparison with free DOX verified by MTT and DAPI staining assays. As the results, we envision that the synthesized P(SEMA-b-NIPAAm-b-VEA) triblock copolymer can be applied as an enhanced anticancer drug delivery nanosystem, mainly due to its smart physicochemical and biocompatibility properties.