Preparation, characterization and in vitro evaluation of cisplatin-bound triblock polymeric micelle solution for ovarian cancer treatment.

The main objective of this study was to prepare cisplatin (CDDP) bound triblock polymeric micelle solution which will have a hydrophilic shell not being phagocytosed by mononuclear phagocyte system, and evaluate in vitro behavior for the treatment of ovarian cancer. For this aim, CDDP was bound to polyglutamic acid (PGA) and the triblock polymer was prepared using polyethylene glycol)-polylactide-co-glycolide (PEG-PLGA). CDDP-bound triblock copolymer conjugation was characterized, in vitro release and permeability studies were performed using USP II method and Caco-2 cell lines, respectively. The release of CDDP from CDDP-bound triblock polymeric micelle solution was found 87.3 ± 3.56% at the end of the 24th hour. CDDP bound triblock polymeric micelle solution was detected as biocompatible, and permeable according to in vitro studies. According to the MTT results, the measured cytotoxicity was found to be maximum in CDDP-bound triblock polymeric micelle solution when compared with CDDP solution and conjugate in SKOV-3 and OVCAR-3 cells, whereas annexin V-FITC apoptosis results were found to be maximum in A2780 cells.

Covalently coupling doxorubicin to polymeric nanoparticles as potential inhaler therapy: in vitro studies.

Lung cancer is the most commonly diagnosed type of cancer worldwide, non-small cell lung cancer accounts for most lung cancers. Doxorubicin is a widely used chemotherapy agent in lung cancer. However, the drug has several undesirable side effects. Here, doxorubicin coupled PEGylated mucoadhesive nanoparticles were designed as a doxorubicin delivery system for pH-triggered release in lung cancer therapy through inhaler administration. Firstly, alginate/chitosan nanoparticles were developed at optimum conditions. Then, PEG diacid bound to structures for doxorubicin binding and providing steric hindrance for phagocytosis. Doxorubicin was linked via an acid-labile amide bond to PEGylated nanoparticles and 444.3 ± 9.2 µg doxorubicin was loaded per mg nanoparticle. Doxorubicin coupled PEG diacid linked alginate/chitosan nanoparticles were checked with FTIR. Hydrodynamic diameter and zeta potential of nanoparticles were measured as 205.7 ± 15.0 nm and -25.17 ± 2.67 mV. The morphology of nanoparticles was evaluated as nearly spherical. Drug release studies were performed both in physiological and acidic media. The drug release from nanoparticles reached 23.6% (pH 5.5) and 18% (pH 7.4) within 48 h. The cytotoxicity experiments were done using A549-luc-C8 cells, also statistical analyzes were carried out. The MTT results indicated the designed drug delivery system possessed anti-tumor efficacy for non-small cell lung cancer therapy.

Brain-targeted, drug-loaded solid lipid nanoparticles against glioblastoma cells in culture.

The aim of this study was the preparation of solid lipid nanoparticles (SLN) formed from cetyl palmitate with having targeting molecules for monocarboxylate transporter-1 (MCT-1): ß-hydroxybutyric acid and anticancer agents: carmustine (BCNU) and temozolomide (TMZ) for enhanced anti-proliferation against glioblastoma multiforme (GBM). Properties including size, morphology, chemical structure, zeta potential, drug encapsulation efficacy, drug release, biocompatibility, stability were determined, and in vitro studies were done. BCNU and TMZ loaded SLNs had a hydrodynamic size of 227 nm ± 46 a zeta potential of -25 mV ± 4 with biocompatible features. The data showed rapid drug release at first and then continuous release. Nanoparticles could be stored for nine months. BCNU and TMZ loaded SLNs exhibited a remarkable increment in the antitumor activity compared to the free-drugs and induced apoptosis on U87MG cells. In addition, targeted nanoparticles were more uptaken by MCT-1 expressing brain cells. This study indicated that BCNU and TMZ loaded SLNs could act as a useful anticancer system for targeted GBM therapy.

One Pot Green Synthesis of Doxorubicin and Curcumin Loaded Magnetic Nanoparticles and Cytotoxicity Studies.

BACKGROUND: Green synthesis, an alternative method for synthesizing nanoparticles, is cheaper, environmentally friendly, and does not show toxic effects. Doxorubicin is a chemotherapeutic agent used in lung cancer. Curcumin is a bioactive compound with properties, such as an anticancer obtained from Curcuma longa. OBJECTIVE: The objective of this study was to develop Doxorubicin and Curcumin loaded magnetic nanoparticles that could be synthesized by green tea leaves and to investigate cytotoxic effects against the A549-luc-C8, non-small cell lung cancer line. METHODS: Magnetic nanoparticles were synthesized with the green synthesis method. Furthermore, Doxorubicin and Curcumin were encapsulated into magnetic nanoparticles with the one-pot method and obtained magnetic nanoparticles characterized using FTIR, SEM/EDX, XRD, and UV-VIS spectrophotometric techniques. After that, The drug release test was performed by dialysis using pH 7.4 phosphate-buffered saline at 37 °C. MTT assay was performed to test the cytotoxicity effect in the A549-luc-C8 cell line. RESULTS: FTIR analysis verified the magnetic structure and drug loading. SEM images of magnetic nanoparticle revealed that they had a size of about 50-60 nm in a mono-disperse manner. Drug release after 24 h was found to be 5.8% for doxorubicin and 3.4% for curcumin, showing controlled release. CONCLUSION: Results showed that the prepared magnetic nanoparticles had a synergistic antitumor activity for A549-luc-C8.

An intravenous application of magnetic nanoparticles for osteomyelitis treatment: An efficient alternative.

The infection of bone and bone marrow is called osteomyelitis. Treatment is difficult since antibiotics can not reach with enough concentration to the infected area. For the first time in this study, we have developed gentamicin-loaded magnetic gelatin nanoparticles (GMGNPs) for nanocarrier-mediated and magnetically targeted osteomyelitis therapy. Gelatin, genipin, and magnetite were used for preparation of that novel carrier system due to their biodegradable and biocompatible properties. Cross-linking degree of gelatin nanoparticles, concentration of magnetite nanoparticles, and adsorbed drug amount were optimized. Furthermore, nanoparticles were characterized and the drug release profile was determined. The osteomyelitis model was constituted in the proximal tibia of rats. The therapeutic potential of GMGNPs on rats was monitored via X-Ray radiography and hematological and histopathological analyses were performed. According to the results, 110.3 ± 8.2 µg gentamicin/mg GMGNPs were used, hydrodynamic size was measured as 253.7 ± 11.8 nm, and GMGNPs have controlled drug release profile. Based on in vivo and ex vivo studies, after six doses of GMGNPs treatment, abscess began to heal and the integrity of periost and bone began to reconstruct. In conclusion, it can be suggested that GMGNPs could provide efficient therapy for osteomyelitis.

Delivery of pemetrexed by magnetic nanoparticles: design, characterization, in vitro and in vivo assessment.

Drug-loaded magnetic nanoparticles have been developed because of the advantages of specific drug targeting in cancer treatment. Pemetrexed (PEM) is a multi-targeting antifolate agent that is effective for the treatment of many cancers, for example, non-small cell lung cancer. Here, PEM loaded magnetic O-carboxymethyl chitosan (O-CMC) nanoparticles were prepared to deliver PEM on tumor tissue with an external magnetic field. The modification of chitosan to O-CMC was confirmed by FTIR analysis. Nanoparticle synthesis was performed via ionic gelation method. The diameter of magnetic O-CMC nanoparticles (MCMC) was found to be 130.1 ± 22.96 nm. After PEM loading, diameter was found to be 123.9 ± 11.42 nm. The drug release of PEM loaded MCMC (PMCMC) was slower in physiological medium than in acidic medium. A549-luc-C8 and CRL5807 cell lines were used for MTT test which showed that IC50 values of nanoparticles were lower than PEM. The antitumor efficiency of PMCMC in xenograft tumor model was examined with in vivo imaging system (IVIS) and caliper and with hematological analyses. In vivo studies revealed that PMCMC had targeted antitumor activity in A549-luc-C8-tumor-bearing mice compared to PEM. As a result, it was suggested that PMCMC have great potential for the treatment of non-small cell lung cancer.

Development of Ultrasound-Triggered and Magnetic-Targeted Nanobubble System for Dual-Drug Delivery.

Non-small cell lung cancer (NSCLC) constitutes more than 85% of lung cancer case. Pemetrexed is used to treat types of NSCLC, and pazopanib is used for some types of soft tissue sarcoma. The aim of the study was development of pemetrexed and pazopanib carrying nanobubble system with magnetic responsiveness and ultrasound sensitivity properties for targeted NSCLC therapy. Drugs were linked to newly designed peptide, and peptide drug conjugates were attached to amine-modified magnetite. Resulting nanoparticles were encapsulated into liposomes, and liposomes were extruded, then nanobubble system was prepared. Moreover, nanobubble biodistribution was monitored by in vivo imaging system. As a result, based on high-performance liquid chromatography data, magnetite and peptide-pemetrexed were conjugated with 54.02% yield, and magnetite and peptide-pazopanib were bound with 63.53% yield. Hydrodynamic size of nanobubbles, prepared from liposomes filtered through 800 nm and 400 nm, was determined as 491.1 ± 130.2 and 275.8 ± 117.8 nm, respectively. Carrier system was accumulated into tumor area with 80.22% yield of the injected carrier system. It was found that nanobubbles were magnetic responsive for accumulation via magnetic field and could be disrupted by ultrasound via focused acoustic pressure, which lead to targeted drug delivery. These nanobubble systems could be investigated for intravenous and inhaler administration in further studies.

In vitro and in vivo evaluation of folate receptor-targeted a novel magnetic drug delivery system for ovarian cancer therapy.

Doxorubicin is widely used anticancer drug; however, use of doxorubicin is limited. Under externally applied magnetic field, magnetic agents can help to transport drug directly to tumor. Folate receptor is overexpressed in ovarian carcinomas. In this study, we aimed to develop magnetically responsive and folate receptor-targeted biomimetic drug delivery system for ovarian cancer therapy. Doxorubicin-loaded and glucose/gluconic acid-coated magnetic nanoparticles were synthesized and erythrocyte membrane vesicles were used for coating of nanoparticles. Folate ligand was anchored to surface so as to target receptor. Hydrodynamic size of nanocarrier was found as 91.2 ± 20.8 nm. The results showed that delivery system has controlled drug release profile and biocompatible features. In folate-free medium, folate receptor-targeted nanocarrier showed 10.33-fold lower IC50 values for A2780 cells and 3.93-fold lower for OVCAR3 cells compared to non-targeted nanoparticles and demonstrated more cytotoxicity against ovarian cancer cells. Moreover, magnetically and folate receptor-targeted doxorubicin delivery system was significantly more effective for therapy of xenografted nude mice than free doxorubicin based on tumor shrinkages and biochemical parameters. In conclusion, it can be suggested that folate ligand-attached and biomimetically designed magnetic drug delivery system have advantages and potential for targeted ovarian cancer therapy.

Development of gemcitabine-adsorbed magnetic gelatin nanoparticles for targeted drug delivery in lung cancer.

Magnetic iron oxide nanoparticles (IONPs) were coated with gelatin type B by means of the two-step desolvation method. Drug loading by adsorption was studied under various conditions such as different temperature, contact time, pH, and initial gemcitabine concentration. Further, Langmuir isotherm curves were constracted and constants were calculated. According to the Langmuir isotherm, the Gibbs free energy of the adsorption process at 25°C was - 4.74 kJ/mol. On the other hand, this value at 37°C was - 7.86 kJ/mol. In vitro drug release was performed at pH levels of 5 and 7.4, with gemcitabine-loaded magnetic gelatin nanoparticles and free gemcitabine, and both the results were subsequently compared.

In vitro evaluation of doxorubicin-incorporated magnetic albumin nanospheres.

Magnetic albumin nanospheres that incorporate doxorubicin (M-DOX-BSA-NPs) were prepared previously by our research group to develop magnetically responsive drug carrier system. This nanocarrier was synthesized as a drug delivery system for targeted chemotherapy. In this work, cytotoxic effects of doxorubicin (DOX)-loaded/unloaded or magnetic/non-magnetic nanoparticles and free DOX against PC-3 cells and A549 cells were determined with the MTT test and the results were compared with each other. DOX-loaded magnetic albumin nanospheres (M-DOX-BSA-NPs) were found more cytotoxic than other formulations. The quantitative data obtained from flow cytometry analysis further verified the higher targeting and killing ability of M-DOX-BSA-NPs than free DOX on both of the cancer cell lines. Additionally, the results of cell cycle analysis have showed that M-DOX-BSA-NPs affected G1 and G2 phases. Finally, cell images were obtained using spin-disk confocal microscopy, and cellular uptake of M-DOX-BSA-NPs was visualized. The findings of this study suggest that M-DOX-BSA-NPs represent a potential doxorubicin delivery system for targeted drug transport into prostate and lung cancer cells.

The effect of pretreatment with substrates on the activity of immobilized pancreatic lipase.

Porcine pancreatic lipase was covalently immobilized on polyvinyl alcohol using adipoyl dichloride as a cross-linker. The effect of pre-treatment of lipase previously with various types of oils on immobilization efficiency was investigated. The increment in immobilization efficiency was observed after pre-treatment of lipases with oils. The highest immobilization efficiency obtained was 20% (v/v) for olive oil pre-treated lipase, which was 8 times higher than that of non-pretreated immobilized lipase. Immobilized lipase had better stability and had some advantages in comparison with free enzyme.

Preparation of magnetically responsive albumin nanospheres and in vitro drug release studies.

In this work, doxorubicin (DOX)-loaded magnetic albumin nanospheres were prepared using desolvation method in order to develop magnetically responsive nanocarrier system. Nanoparticles were characterized with zetasizer, SEM, AFM, XRD and magnetometer. In vitro DOX release was also investigated. It was found that nanoparticles had spherical shape with narrow size distributions and had magnetic responsiveness. In addition, slower drug release was observed with nanoparticulate system compared with free DOX. Moreover, the release rate should accelerate at target sites (cancer cells or tissue) where proteolytic enzymes are more abundant as known; therefore, magnetic albumin nanospheres can be effective potential DOX carrier with targeting ability.

Removal of textile dye, direct red 23, with glutaraldehyde cross-linked magnetic chitosan beads.

One of the most important classes of pollutants is dyes, and today there are more than 100,000 commercial dyes. Conventional treatment processes are very expensive, so it is essential to develop low-cost sorbent materials with high adsorption capacities. The aim of this study is to prepare magnetic microsized adsorbents that have high adsorption capacity for removal of direct red 23. Through this objective, glutaraldehyde cross-linked magnetic chitosan beads were formed in order to remove the textile dye direct red 23. Barium ferrite was used to give a magnetic property so that the beads could easily be separated from the water after treatment. The effects of barium ferrite, pH, incubation time, dye concentration, and glutaraldehyde amounts were investigated. The Langmuir and Freundlich adsorption models were applied to describe the equilibrium isotherms. The adsorption capacity had a very large value: 1250 mg/g at pH 4.0, at room temperature. Compared with activated carbon, magnetic cross-linked chitosan exhibits excellent performance in the adsorption of anionic dyes and the magnetic properties of beads enable us to remove the beads from the water after treatment. Pseudo-second-order and intraparticle diffusion kinetic models were applied.

Synthesis of folate receptor-targeted and Doxorubicin-coupled chemotherapeutic nanoconjugate and research into its medical applications.

Folate-targeted drug delivery has become an alternative therapy for the treatment of various cancers. Folate receptors are known to be responsible for cellular accumulation of folate and folate analogs with high binding affinity. The anthracycline antibiotic doxorubicin has a broad spectrum of antineoplastic action and a correspondingly widespread degree of clinical use. In this work, we aimed to prepare a folate receptor-targeted doxorubicin delivery system to achieve minimal effect of doxorubicin on healthy cells and more cytotoxicity of it on tumor cells. Folate-poly(ethylene glycol)-doxorubicin (FOL-PEG-DOX) nanoconjugate was synthesized through this aim and characterized with nuclear magnetic resonance (NMR), zetasizer, and atomic force microscopy (AFM). Doxorubicin release studies were also performed in vitro. The size of FOL-PEG-DOX was 78.84 nm. The results indicated that doxorubicin release rate from the conjugate was faster at pH 5.0 than pH 7.4 and the amide bond between DOX and PEG was more stable at pH 7.4 than pH 5.0. As a consequence, FOL-PEG-DOX nanoconjugate could be a potentially useful delivery system for folate receptor-positive cancer cells.

Radiolabeling of folate targeted multifunctional conjugate with Technetium-99m and biodistribution studies in rats.

Despite the progress in the diagnosis and management of early stage disease, the management of advanced prostate cancer remains an important problem. Prostate tissue expresses folate receptor (FR) which binds both folic acid and folate-linked drugs or imaging agents. Doxorubicin is the best known and most widely used member of the anthracycline antibiotic group of anticancer agents. The aim of this work is to develop a multifunctional nanoconjugate, (99m)Tc-folate-PEG-doxorubicin, in order to investigate its radiopharmaceutical potential as a prostate cancer imaging and real-time drug location imaging agent. Through this aim, biodistribution studies of (99m)Tc-folate-PEG-doxorubicin and control groups ((99m)Tc-doxorubicin and (99m)Tc-PEG-doxorubicin) in male rats were carried out. Obtained data showed that uptake of (99m)Tc-folate-PEG-doxorubicin in prostate was significantly higher than that of the control groups due to the affinity of folate ligand to folate receptor. As a consequence, it was indicated that (99m)Tc-FOL-PEG-DOX radiolabeled conjugate which has a great target/non-target organ ratio, is specific for target organ and has a high radiopharmaceutical potential as a prostate cancer and real-time drug location imaging agent.