Multimodality treatment of cancer with herceptin conjugated, thermomagnetic iron oxides and docetaxel loaded nanoparticles of biodegradable polymers.

We developed a system of nanoparticles of poly(lactide)-d-α-tocopheryl polyethylene glycol succinate (PLA-TPGS) and carboxyl group-terminated TPGS (TPGS-COOH) copolymer blend for multimodality treatment of cancer, which formulated docetaxel for chemotherapy, herceptin for biotherapy and targeting, and iron oxides (IOs) for hyperthermia therapy, which are denoted as MMNPs. It is demonstrated that the MMNPs achieved a significantly higher therapeutic effects than the various combination of the corresponding individual modality treatment NPs and the dual modality treatment NPs due to the synergistic effects among the chemo, bio, and thermo therapies. We further developed a method by employing the concept of NPs IC50, the concentration of the agent-, or agents-loaded nanoparticles that is needed to kill 50% of the cancer cells, to quantitatively access the synergistic effects of the multimodality treatment. It is shown by employing the SK-BR-3 cell line as an in vitro model of the HER2-positive breast cancer that the NPs IC50 is 0.42 mg/mL DCL-NPs plus 1.33 mg/mL Her-NPs plus 0.59 mg/mL IOs-NPs, a total NPs concentration of 2.34 mg/mL for the treatment of a physical mixture of the DCL-NPs, Her-NPs and IOs-NPs at the 1:2:7 weight ratio, while it is only 0.0011 mg/mL for the MMNPs for 24 h, which is 2130 fold more efficient than the physical mixture of the corresponding single modality treatments.

Thermochemotherapy mediated by novel solar-planet structured magnetic nanocomposites for glioma treatment.

Cancer comprehensive treatment has been fully recognized as it can provide an effective multimodality approach for fighting cancers. This work evaluates the effects of a kind of novel solar-planet structured magnetic nanocomposites (MNCs) for magnetic thermochemotherapy. Amino silane coated magnetic nanoparticles (MNPs) as agent of magnetic mediated hyperthermia (MMH) for cancer treatment were prepared by the chemical precipitation method. Docetaxel (an anticancer drug) loaded polymeric nanoparticles (DNPs) composed of carboxylic-terminated poly (D,L-lactic-co-glycolic acid) (PLGA) with Vitamin E TPGS as emulsifier for sustained drug release were prepared by a modified solvent extraction/evaporation technique. Furthermore, the MNPs modified with amino groups could be covalently attached to the surface of carboxylic terminated DNPs to form the so-called solar-planet structured MNCs by 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) crosslinking. The prepared solar-planet structure has been confirmed by fluorescent observation. Inductive heating property of the nanocomposite was evaluation by monitoring the temperature increase of the MNCs suspension under alternative magnetic field (AMF). Drug encapsulation efficacy and drug release of the magnetic nanocomposite were conducted by high performance liquid chromatography (HPLC). In vitro evaluation of the novel nanocomposite as mediator for thermochemotherapy was conducted on the U251 human glioma cells and the synergistic effect between MMH and docetaxel chemotherapy was confirmed. All the observation supports that solar-planet structured MNC is a novel and effective mediator for magnetic thermochemotherapy. The MNCs can realize cancer comprehensive treatment thus has great potential in clinical application.

Vitamin E (D-alpha-tocopheryl-co-poly(ethylene glycol) 1000 succinate) micelles-superparamagnetic iron oxide nanoparticles for enhanced thermotherapy and MRI.

We synthesized vitamin E TPGS (d-α-Tocopheryl-co-poly(ethylene glycol) 1000 succinate) micelles for superparamagnetic iron oxides formulation for nanothermotherapy and magnetic resonance imaging (MRI), which showed better thermal and magnetic properties, and in vitro cellular uptake and lower cytotoxicity as well as better in vivo therapeutic and imaging effects in comparison with the commercial Resovist and the Pluronic F127 micelles reported in the recent literature. The superparamagnetic iron oxides originally coated with oleic acid and oleylamine were formulated in the core of the TPGS micelles using a simple solvent-exchange method. The IOs-loaded TPGS showed greatest colloidal stability due to the critical micelle concentration (CMC) of vitamin E TPGS. Highly monodisperse and water soluble suspension was obtained which were stable in 0.9% normal saline for a period of 12 days. The micelles were characterized for their size and size distribution. Their morphology was examined through transmission electron microscopy (TEM). The enhanced thermal and superparamagnetic properties of the IOs-loaded TPGS micelles were assessed. Cellular uptake and cytotoxicity were investigated in vitro with MCF-7 cancer cells. Relaxivity study showed that the IOs-loaded TPGS micelles can have better effects for T2-weighted imaging using MRI. T2 mapped images of xenograft grown on SCID mice showed that the TPGS micelle formulation of IOs had ∼1.7 times and ∼1.05 times T2 decrease at the tumor site compared to Resovist and the F127 micelle formulation, respectively.

Formulation of Docetaxel by folic acid-conjugated d-α-tocopheryl polyethylene glycol succinate 2000 (Vitamin E TPGS(2k)) micelles for targeted and synergistic chemotherapy.

Although high efficacy has been showed, Paclitaxel and Docetaxel cause serious side effects due to the adjuvant used in their clinical formulation Taxol® and Taxotere®. We developed a micelle system with a newly synthesized TPGS(2k) polymer, which shows lower CMC of 0.0219 mg/ml compared with 0.2 mg/ml for traditional micelles with TPGS involved, to achieve sustained and controlled drug delivery with Docetaxel used as a model anti-cancer drug. The TPGS(2k) micelles were further conjugated to folic acid (FA) for targeted drug delivery. The Docetaxel-loaded TPGS(2k) micelles with and without FA conjugation were found of desired size and size distribution, high drug encapsulation efficiency and favorable drug release. In vitro studies using MCF-7 cancer cells demonstrated significantly the higher cellular uptake of the formulated drug for TPGS(2k) micelle formulation than that for Taxotere®. The targeting effects for the FA conjugated TPGS(2k) micelles are also demonstrated. The IC50 value, which is the drug concentration needed for 50% cell viability in the designated time period, is 103.4, 1.280 and 0.1480 µg/ml for MCF-7 cancer cells after 24, 48, and 72 h treatment respectively, which is greatly decreased to be 0.526, 0.251 and 0.233 µg/ml, i.e. a 99.5%, 80.4% decrease and 57.5% increase for the TPGS(2k) micelle formulation, and further decreased to be 0.1780, 0.1520 and 0.1140 µg/ml, i.e. a 99.8%, 88.1% and 23.0% decrease for the folic acid conjugated micelles, respectively. A synergistic effect between TPGS(2k) and Docetaxel is also achieved. The present work represents a new concept in the design of drug delivery systems--the carrier materials of the drug delivery system can also have therapeutic effects, which either modulate the side effects of, or promote a synergistic interaction with the formulated drug.

Facile synthesis of water-stable magnetite nanoparticles for clinical MRI and magnetic hyperthermia applications.

AIMS: Superparamagnetic magnetite nanoparticles have been under intensive investigation in nanomedicine. However, it is still a challenge to synthesize high-quality water-stable magnetite nanoparticles for better magnetic performance and less side effects in medical MRI and nanothermotherapy. MATERIALS & METHODS: We successfully synthesized hydrophilic magnetite nanoparticles through thermal decomposition of Fe(acac)(3) in triethylene glycol, which were coated with a triethylene glycol layer and thus demonstrated excellent water stability. RESULTS: The optimized deposition temperature has been found to be 250°C (IO-250 NPs). The magnetic and thermal properties as well as the cytotoxicity of IO-250 NPs were investigated. In vitro experiments have demonstrated high cellular uptake and low cytotoxicity. The hyperthermia experiments showed effectiveness in temperature rise and cancer cell death. IO-250 NPs showed promising MRI with relaxivity r(2)* as high as 617.5 s(-1) mM(-1) Fe. In vivo MRI showed excellent tumor imaging. CONCLUSION: The IO-250 NPs have great potential to be applied for clinical MRI and magnetic thermotherapy.

In vitro investigation on poly(lactide)-Tween 80 copolymer nanoparticles fabricated by dialysis method for chemotherapy.

Polysorbate 80 (Tween 80) has been widely used as an emulsifier with excellent effects in nanoparticles technology for biomedical applications. This work was thus triggered to synthesize poly(lactide)/Tween 80 copolymers with various copolymer blend ratio, which were synthesized by ring-opening polymerization and characterized by 1H NMR and TGA. Nanoparticles of poly(lactide)/Tween 80 copolymers were prepared by the dialysis method without surfactants/emulsifiers involved. Paclitaxel was chosen as a prototype anticancer drug due to its excellent therapeutic effects against a wide spectrum of cancers. The drug-loaded nanoparticles of poly(lactide)/Tween 80 copolymers were then characterized by various state-of-the-art techniques, including laser light scattering for particles size and size distribution, field emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM) for surface morphology; laser Doppler anemometry for zeta potential; differential scanning calorimetry (DSC) for the physical status of the drug encapsulated in the polymeric matrix; X-ray photoelectron spectrometer (XPS) for surface chemistry; high performance liquid chromatography (HPLC) for drug encapsulation efficiency; and in vitro drug release kinetics. HT-29 cells and Glioma C6 cells were used as an in vitro model of the GI barrier for oral chemotherapy and a brain cancer model to evaluate in vitro cytotoxicity of the paclitaxel-loaded nanoparticles. The viability of C6 cells was decreased from 37.4 +/- 4.0% for poly(D,L-lactide-co-glycolic acid) (PLGA) nanoparticles to 17.8 +/- 4.2% for PLA-Tween 80-10 and 12.0 +/- 5.4% for PLA-Tween 80-20 copolymer nanoparticles, which was comparable with that for Taxol at the same 50 microg/mL drug concentration.

In vitro and in vivo studies on vitamin E TPGS-emulsified poly(D,L-lactic-co-glycolic acid) nanoparticles for paclitaxel formulation.

This work shows a full spectrum of research on Vitamin E TPGS-emulsified Poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for paclitaxel formulation to improve its therapeutic index and to reduce the adverse effects of adjuvant Cremophor EL in its current clinical formulation of Taxol. Paclitaxel-loaded PLGA NPs were prepared by a modified solvent extraction/evaporation technique with vitamin E TPGS as emulsifier. The formulated NPs were found in quite uniform size of approximately 240 nm diameter. The in vitro drug release profile exhibited a biphasic pattern with an initial burst followed by a sustained release. In vitro HT-29 cell viability experiment demonstrated that the drug formulated in the NPs was 5.64, 5.36, 2.68, and 1.45 times more effective than that formulated in the Taxol formulation after 24, 48, 72, 96 h treatment, respectively at 0.25 microg/mL drug concentration, which should be even better with the sustainable release feature of the NPs formulation considered. In vivo PK measurement confirmed the advantages of the NP formulation versus Taxol. The area-under-the-curve (AUC) for 48 h for Vitamin E TPGS emulsified PLGA NP formulation of paclitaxel were found 3.0 times larger than that for the Taxol formulation. The sustainable therapeutic time, at which the drug concentration drops below the minimum effective value, for the NP formulation could be 1.67 times longer than that for the Taxol formulation.

Nanoparticles of biodegradable polymers for clinical administration of paclitaxel.

Paclitaxel is one of the best antineoplastic drugs found from nature in the past decades, which has been found effective against a wide spectrum of cancers including ovarian cancer, breast cancer, small and non small cell lung cancer, colon cancer, head and neck cancer, multiple myeloma, melanoma, and Kaposi's sarcoma. Like many other anticancer drugs, it has difficulties in clinical administration due to its poor solubility in water and most pharmaceutical reagents. In its current clinical application, an adjuvant called Cremophor EL has to be employed, which has been found to be responsible for many serious side effects. Nanoparticles of biodegradable polymers can provide an ideal solution to such an adjuvant problem and realize a controlled and targeted delivery of the drug with better efficacy and less side effects. With further development, such as particle size optimization and surface coating, nanoparticle formulation of paclitaxel can promote a new concept of chemotherapy to realize its full efficacy and to improve quality of life of the patients, which includes personalized chemotherapy, local chemotherapy, sustained chemotherapy, oral chemotherapy, chemotherapy across the blood-brain barrier, chemotherapy across the microcirculation barrier, etc. The present research proposes a novel formulation for fabrication of nanoparticles of poly(lactic-co-glycolic acid) (PLGA) by a modified solvent extraction/evaporation technique, in which natural emulsifiers, such as phospholipids, cholesterol and vitamin E TPGS are creatively applied to achieve high drug encapsulation efficiency, desired drug released kinetics, high cell uptake and high cytotoxicity. The nanoparticles composed of various recipes and manufactured under various conditions were characterized by laser light scattering (LLS) for size and size distribution, scanning electron microscopy (SEM) and atomic force microscopy (AFM) for morphological properties, X-ray photoelectron spectroscopy (XPS) and Fourier Transformation Infrared Spectroscopy (FTIR) for surface chemistry, zeta-potential for surface charge, and differential scanning calorimetry (DSC) for the thermogram properties. The drug encapsulation efficiency and the drug release kinetics under in vitro conditions were measured by high performance liquid chromatography (HPLC). It was found that these natural emulsifiers have great advantages for nanoparticle formulation of paclitaxel over the traditional macromolecular emulsifiers, such as polyvinyl alcohol (PVA). Nanoparticles of desired small size and narrow size distribution can be obtained. The drug encapsulation efficiency can be achieved as high as 100 %. The released kinetics can be made under control. The HT-29 cancer cell line experiment showed that after 24 hours of incubation, the cell mortality caused by the drug administered by such nanoparticle formulation could be more than 13 times higher than that caused by the free drug under similar conditions.