Complete ablation of tumors using synchronous chemoradiation with bimetallic theranostic nanoparticles.

Synchronous chemotherapy and radiotherapy, termed chemoradiation therapy, is now an important standard regime for synergistic cancer treatment. For such treatment, nanoparticles can serve as improved carriers of chemotherapeutics into tumors and as better radiosensitizers for localized radiotherapy. Herein, we designed a Schottky-type theranostic heterostructure, Bi2S3-Au, with deep level defects (DLDs) in Bi2S3 as a nano-radiosensitizer and CT imaging contrast agent which can generate reactive free radicals to initiate DNA damage within tumor cells under X-ray irradiation. Methotrexate (MTX) was conjugated onto the Bi2S3-Au nanoparticles as a chemotherapeutic agent showing enzymatic stimuli-responsive release behavior. The designed hybrid system also contained curcumin (CUR), which cannot only serve as a nutritional supplement for chemotherapy, but also can play an important role in the radioprotection of normal cells. Impressively, this combined one-dose chemoradiation therapeutic injection of co-drug loaded bimetallic multifunctional theranostic nanoparticles with a one-time clinical X-ray irradiation, completely eradicated tumors in mice after approximately 20 days after irradiation showing extremely effective anticancer efficacy which should be further studied for numerous anti-cancer applications.

Improved synergic therapeutic effects of chemoradiation therapy with the aid of a co-drug-loaded nano-radiosensitizer under conventional-dose X-ray irradiation.

The goal of this work is to harness the advantages of a targeted hybrid nanostructure, BSA-coated Fe3O4 (F)-Au heterodimer, as a radiosensitizer and co-delivery vehicle of chemotherapeutic drugs for enhanced synergic cancer therapy and protection of healthy tissues. F-Au-BSA-MTX-CUR combines the abilities of enhanced X-ray radiation therapy (F-Au), long blood circulation time (BSA), tumor targeting (MTX), enhanced chemotherapy (MTX and CUR), and protection of normal cells against the harmful effects of radiation (CUR). In this work, we present the radioprotective and radiosensitizing effects of CUR on normal tissues and the tumor site, respectively. After technical evaluation, drug loading, drug release behavior, hemolysis assay, transfection efficacy, and cellular uptake studies with fluorescence microscopy, the biosafety and toxicity of the nanostructure was assessed in vitro and in vivo. Also, to confirm its power to improve synergistic chemoradiation therapy in mice, the antitumor effects of the designed treatment plan were assessed in a 4T1-tumor bearing mouse model. The in vivo antitumor effect evaluation interestingly reveals outstanding therapeutic power of the final formulation (F-Au-BSA-MTX-CUR) and further requirement of CUR as a radioprotective. This result importantly revealed the radioprotection effect of CUR. Co-delivery of the chemotherapeutic drugs MTX and CUR, combined with the radiosensitizing effect of the F-Au heterodimer and the radioprotective effect of CUR, showed promising prospects in cancer therapy.

Methotrexate anticancer drug delivery to breast cancer cell lines by iron oxide magnetic based nanocarrier.

In this study, we have achieved to provide an efficient method for production of iron oxide magnetic nanoparticles (MNPs) with arginine capping using in situ and one-pot co-precipitation method. As a novel drug delivery system, methotrexate (MTX) was conjugated to the obtained nanoparticles. These MNPs conjugate can potentially use in controlled drug delivery as carrier, and in magnetic resonance imaging as a contrast agent. Also, these nanoparticles can serve as a target in cancer therapy and diagnosis. These MNPs were covalently bond with MTX and can target the majority of cancer cells that their surfaces overexpressed by folate receptors. These conjugated nanoparticles were obtained through amide bond between the amine groups on their surface and the carboxylic acid end groups on MTX due to being functionalized with arginine. MTX was cleaved from nanoparticles according to drug release experiments in the presence of protease-like lysosomal conditions. Fe-Arg-MTX was characterized by transmission electron microscopes, dynamic light scattering, thermogravimetric analysis, differential scanning calorimetry, X-ray diffraction, and Fourier transform infrared spectroscopy. Furthermore, vibrating sample magnetometry analysis showed excellent magnetic properties of them. The average particle size of Fe-Arg-MTX was approximately 27 nm. The result revealed that the bare nanoparticles have no cytotoxicity against MCF-7, 4T1, and HFF-2 cell lines. Hemolysis assay showed that these nanoparticles are biocompatible. Regarding the research success, an efficient technique can be presented for drug delivery and controlled release and for studying cancer-fighting in alive creature's bodies.

In vitro and in vivo delivery of artemisinin loaded PCL-PEG-PCL micelles and its pharmacokinetic study.

Artemisinin (ART) is a natural anti-malarial sesquiterpene lactone with anticancer properties, but its application is limited because of its low water solubility. To increase the bioavailability and water solubility of ART, we synthesized three series of poly (ɛ-caprolactone)-poly (ethylene glycol)-poly (ɛ-caprolactone) (PCL-PEG-PCL) tri-block copolymers. The structure of the copolymers was characterized by HNMR, FTIR, DSC and GPC techniques. ART was encapsulated inside micelles by a nanoprecipitation method which leading to the formation of ART/PCL-PEG-PCL micelles. The obtained micelles were characterized by DLS and AFM technique. The results showed that the average size of micelles was about 83.22 nm. ART was encapsulated into PCL-PEG-PCL micelles with encapsulation efficacy of 89.23 ± 1.41%. In vivo results demonstrated that this formulation significantly increased drug accumulation in tumours. Pharmacokinetic study in rats revealed that in vivo drug exposure of ART was significantly increased and prolonged by intravenously administering ART-loaded micelles when compared with the same dose of free ART. The MTT assay showed that bare PCL-PEG-PCL micelles is non-toxic to MCF7 and 4T1 cancer cell lines whereas the ART/PCL-PEG-PCL micelles showed a specific toxicity to both cancer cell lines. Therefore, the polymeric micellar formulation of ART based copolymer could provide a desirable process for ART delivery.

Pharmacokinetics and in vitro and in vivo delivery of sulforaphane by PCL-PEG-PCL copolymeric-based micelles.

A reliable and efficient drug delivery system using PCL-PEG-PCL copolymers was established for the anti-cancer compound sulforaphane (SF) in this study. Encapsulated SF by PCL-PEG-PCL nanoparticles led to formation of SF-loaded PCL-PEG-PCL micelles. Micelles characterization and stability, the particle size and their morphology were determined by DLS and AFM. The loading efficiency of SF was 19.33 ± 1.28%. The results of AFM showed that the micelles had spherical shapes with the size of 107 nm. In vitro release of SF from SF-entrapped micelles was remarkably sustained. The cytotoxicity of free SF, PCL-PEG-PCL and SF/PCL-PEG-PCL micelles was analysis by MTT colorimetric assay on MCF-7, 4T1 and MCF10A cell lines. Expression levels of BCL-2, PARP, COX-2, Caspase-9 and ACTB genes were quantified by real-time PCR. Flow cytometry analysis was performed using the Annexin V-FITC Apoptosis Detection Kit to evaluate the apoptotic effects of free SF compared with SF/PCL-PEG-PCL micelles. Study of the in vivo pharmacokinetics of the SF-loaded micelles was carried out on SF-loaded PCL-PEG-PCL micelles in comparison with free SF. The results of in vivo experiments indicated that the SF loaded micelles significantly reduced the tumor size. In vivo results showed that the multiple injections of SF-loaded micelles could prolong the circulation period and increase the therapeutic efficacy of SF. Also, in comparison with the free-SF solution, encapsulation of the SF in micelles increased the mean residence time from 0.5 to 4 h and the area under the concentration-time curve up to 50 folds.

Pharmacokinetics and in vivo delivery of curcumin by copolymeric mPEG-PCL micelles.

Curcumin (CUR) has been associated with anti-inflammatory, antimicrobial, antioxidant, anti-amyloid, and antitumor effects, but its application is limited because of its low aqueous solubility and poor oral bioavailability. To progress the bioavailability and water solubility of CUR, we synthesized five series of mono methoxy poly (ethylene glycol)-poly (ε-caprolactone) (mPEG-PCL) diblock copolymers. The structure of the copolymers was characterized by H NMR, FTIR, DSC and GPC techniques. In this study, CUR was encapsulated within micelles through a single-step nano-precipitation method, leading to formation of CUR-loaded mPEG-PCL (CUR/mPEG-PCL) micelles. The resulting micelles were characterized further by various techniques such as dynamic light scattering (DLS) and atomic force microscopy (AFM). The cytotoxicity of void CUR, mPEG-PCL and CUR/mPEG-PCL micelles was compared to each other by performing MTT assay of the treated MCF-7 and 4T1 cell line. Study of the in vivo pharmacokinetics of the CUR-loaded micelles was also carried out on selected copolymers in comparison with CUR solution formulations. The results showed that the zeta potential of CUR-loaded micelles was about -11.5mV and the average size was 81.0nm. CUR was encapsulated into mPEG-PCL micelles with loading capacity of 20.65±0.015% and entrapment efficiency of 89.32±0.34%. The plasma AUC (0-t), t1/2 and Cmax of CUR micelles were increased by 52.8, 4.63 and 7.51-fold compared to the CUR solution, respectively. In vivo results showed that multiple injections of CUR-loaded micelles could prolong the circulation time and increase the therapeutic efficacy of CUR. These results suggested that mPEG-PCL micelles would be a potential carrier for CUR.