Synthesis, in silico metabolic and toxicity prediction of some novel imidazolinones derivatives as potent anticonvulsant agents.

A series of 1,2,4-trisubstituted 5-imidazolinone derivatives were synthesized by Erlenmeyer condensation of benzoylglycine (hippuric acid) with different aldehydes in the presence of sodium acetate and acetic anhydride. The derivatives of the compounds were prepared by condensation of some known sulpha drugs with 5-oxazolone derivatives. The anticonvulsant activity of the compounds was determined by the protection of pentylenetetrazole-induced convulsions that was ranged from 10 to 60%. The compounds with p-OCH3, p-OH and o-Cl substitutions in the phenyl ring on 4(th) position of the imidazolinone ring exhibited good anticonvulsant activity. In silico metabolic and toxicity studies showed that all the compounds in the series are not likely to exhibit toxicity except the compounds IIIa, IIIb, VIa and VIb, that is predicted to show 29% mutagenicity and 53% irritation in comparison to the other compounds. The predicted lethal effect and hERG toxicity of the compounds showed that IIa, IVa, Va and Vb might be toxic at higher concentrations. The results successfully establish the synthesized imidazolinone derivatives as novel compounds with anticonvulsant properties, low predicted cardiotoxicity and lethal effects thus can be promising leads for further development as novel anticonvulsants.

Improved T(1)-weighted dynamic contrast-enhanced MRI to probe microvascularity and heterogeneity of human glioma.

Dynamic contrast-enhanced (DCE) T(1)-weighted magnetic resonance imaging (MRI) is a powerful tool capable of providing quantitative assessment of contrast uptake and characterization of microvascular structure in human gliomas. The kinetics of the bolus injection doped with increasing concentrations of gadopentate dimeglumine (Gd-DTPA) depends on tissue as well as pulse sequence parameters. A simple method is described that overcomes the limitation of relative signal increase measurement and may lead to improved accuracy in quantification of perfusion indices of glioma. Based on an analysis of the contrast behavior of spoiled gradient-recalled echo sequence; a parameter K with arbitrary unit 5.0 is introduced, which provides a better approximation to the differential T(1) relaxation rate. DCE-MRI measurements of relative cerebral blood volume (rCBV) and cerebral blood flow (rCBF) were calculated in 25 patients with brain tumors (15=high-grade glioma, 10=low-grade glioma). The mean rCBV was 6.46 +/- 2.45 in high-grade glioma and 2.89 +/- 1.47 in the low-grade glioma. The rCBF was 3.94 +/- 1.47 in high-grade glioma while 2.25 +/- 0.87 in low-grade glioma. A significant difference in rCBF and rCBV was found between high- and low-grade gliomas. This simple and robust technique reveals the complexity of tumor vasculature and heterogeneity that may aid in therapeutic management especially in nonenhancing high-grade gliomas. We conclude that the precontrast medium steady-state residue parameter K may be useful in improved quantification of perfusion indices in human glioma using T(1)-weighted DCE-MRI.

Formulation and in vitro evaluation of 17-allyamino-17-demethoxygeldanamycin (17-AAG) loaded polymeric mixed micelles for glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in human. 17-Allylamino-17-demethoxy geldanamycin (17-AAG) is an inhibitor of heat shock protein 90 (HSP90). The highly lipophilic nature and selective targeting of tumor cells makes 17-AAG a promising candidate for therapy of GBMs but poor water solubility, short biological half-life and hepatotoxicity limited its clinical use. Polymeric mixed micelles composed of Pluronic® P-123 and F-127 (2:1 (w/w)) containing 17-AAG were prepared and characterized. Cellular uptake and in vitro cytotoxicity of the prepared micelles were determined in U87MG human glioblastoma cells. The particle size of 17-AAG loaded Pluronic(®) P-123 and F-127 mixed micelles was 22.2 ± 0.1 nm; drug loading was about 4.0 ± 0.5% (w/w) with 88.2 ± 3.1% (w/w) encapsulation efficiency. About 90% of drug was released from the nanoparticles over 8 days. Cellular uptake studies showed intracellular uptake of mixed micelles. Cytotoxicity study showed 5-fold increase (P < 0.05, n = 3) in the cytotoxicity of 17-AAG-loaded mixed micelles to free 17-AAG. Due to their targeting ability, size, high drug loading and controlled release behavior, 17-AAG loaded Pluronic(®) P-123 and F-127 mixed micelles might be developed as a delivery system for GBM treatment.

Polymeric mixed micelles for delivery of curcumin to multidrug resistant ovarian cancer.

UNLABELLED: The biggest challenge for the treatment of multidrug resistance cancer is to deliver high concentration of anticancer drugs specifically to cancer cells for longer period of time. Poloxamers and D-alpha-Tocopheryl polyethylene glycol 1000 succinate (TPGS) are known inhibitors of P-glycoprotein. Mixed micelles prepared from Poloxamer 407 and TPGS may increases the therapeutic efficacy of drug by delivering high concentration of drug inside the cells and inhibition of P-gp. Curcumin (CUR) is a naturally derived novel anticancer agent but poor solubility limited its clinical use. In this study, we have developed Poloxamer 407 and TPGS mixed micelle encapsulating CUR for treatment of multidrug-resistant ovarian cancer. CUR-loaded Poloxamer 407/TPGS mixed micelles were prepared by thin film hydration method and their physicochemical properties were characterized. Cellular uptake and in vitro cytotoxicity of the CUR-loaded Poloxamer 407/TPGS mixed micelles were studied in multidrug-resistant ovarian cancer (NCI/ADR-RES) cells. The diameter of CUR-loaded Poloxamer 407/TPGS mixed micelles was about 21.4 +/- 0.3 nm and a zeta potential of -11.56 +/- 0.7 mV. The encapsulation efficiency of CUR was ranged from 95-86% with drug loading was about 1-9%. Differential scanning calorimetry and X-ray powder diffraction studies confirmed that CUR was encapsulated by the polymers. The in vitro release studies showed that mixed micelles sustained the release of CUR for more than 9 days. Results from cellular uptake studies indicated that CUR-loaded Poloxamer 407/TPGS mixed micelles had increased cellular uptake of CUR in NCI/ADR-RES cells. Cytotoxicity of CUR-loaded Poloxamer 407/TPGS mixed micelles was found to be 3 folds more than free CUR after 48 of incubations. CONCLUSION: This study suggests that Poloxamer 407/TPGS mixed micelles might be a suitable nanocarrier for curcumin to treat multidrug resistant ovarian cancer.

Zirconium phosphate nanoplatelets: a biocompatible nanomaterial for drug delivery to cancer.

The objective of this study was to evaluate the biocompatibility of zirconium phosphate (ZrP) nanoplatelets (NPs), and their use in drug delivery. ZrP and doxorubicin-intercalated ZrP (DOX:ZrP) NPs were characterized by using X-Ray Powder Diffraction (XRPD), Thermogravimetric Analysis (TGA), Transmission Electron Micrography (TEM), Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM). Biocompatibility of ZrP NPs was evaluated in human embryonic kidney (HEK-293), breast cancer (MCF-7), metastatic breast cancer (MDA-MB-231), ovarian cancer (OVCAR-3), resistant cancer (NCI-RES/ADR) cells and mouse macrophage (RAW 264.7) cell lines. Hemocompatibility of ZrP NPs was evaluated with human red blood cells. Simulated body fluid (SBF) of pH 7.4 was used to determine the in vitro release of doxorubicin from DOX:ZrP NPs. Cellular uptake and in vitro cytotoxicity studies of DOX:ZrP NPs were determined in MDA-MB-231. The ZrP nanomaterial can be prepared in the 100-200 nm size range with a platelet-like shape. The ZrP NPs themselves are biocompatible, hemocompatible and showed no toxicity to the macrophage cells. ZrP NPs can intercalate high loads (35% w/w) of doxorubicin between their layers. The release of DOX was sustained for about 2 weeks. DOX:ZrP NPs showed higher cellular uptake and increased cytotoxicity than free DOX in MDA-MB-231 cells. ZrP NPs are highly biocompatible, can intercalate large amounts of drugs and sustain the release of drugs. ZrP NPs improved the cellular uptake and cytotoxicity of DOX to MDA-MB-231 cells. ZrP NPs are promising nanocarriers for drug delivery in cancer therapy.

Poloxamer 407/TPGS mixed micelles for delivery of gambogic acid to breast and multidrug-resistant cancer.

BACKGROUND: Delivery of a high concentration of anticancer drugs specifically to cancer cells remains the biggest challenge for the treatment of multidrug-resistant cancer. Poloxamers and D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) are known inhibitors of P-glycoprotein (P-gp). Mixed micelles prepared from Poloxamer 407 and TPGS may increase the therapeutic efficacy of the drug by delivering high concentrations inside the cells and inhibiting P-gp. Gambogic acid (GA) is a naturally derived novel anticancer agent, but poor solubility and toxic side effects limit its use. In this study, we have developed Poloxamer 407 and TPGS mixed micelle-encapsulating GA for the treatment of breast and multidrug-resistant cancer. METHODS: GA-loaded Poloxamer 407/TPGS mixed micelles were prepared using a thin film hydration method, and their physicochemical properties were characterized. Cellular accumulation and cytotoxicity of the GA-loaded Poloxamer 407/TPGS mixed micelles were studied in breast cancer cells, MCF-7 cells, and multidrug-resistant NCI/ADR-RES cells. RESULTS: The diameter of GA-loaded Poloxamer 407/TPGS mixed micelles was about 17.4 ± 0.5 nm and the zeta potential -13.57 mV. The entrapment efficiency of GA was 93.1% ± 0.5% and drug loading was about 9.38% ± 0.29%. Differential scanning calorimetry and X-ray powder diffraction studies confirmed that GA is encapsulated by the polymers. The in vitro release studies showed that mixed micelles sustained the release of GA for more than 4 days. Results from cellular uptake studies indicated that GA-loaded Poloxamer 407/TPGS mixed micelles had increased cellular uptake of GA in NCI/ADR-RES cells. Cytotoxicity of GA-loaded Poloxamer 407/TPGS mixed micelles was found to be 2.9 times higher in multidrug-resistant NCI/ADR-RES cells, and 1.6 times higher in MCF-7 cells, as compared with unencapsulated GA. CONCLUSION: This study suggests that Poloxamer 407/TPGS mixed micelles can be used as a delivery system for GA to treat breast and multidrug-resistant cancer.

Folate receptor targeted 17-allylamino-17-demethoxygeldanamycin (17-AAG) loaded polymeric nanoparticles for breast cancer.

Low water solubility and hepatotoxicity limited the clinical use of 17-allylamino-17-demethoxy geldanamycin (17-AAG), an inhibitor of heat shock protein 90 (HSP90). Folate targeted polylactide-co-glycolide-polyethylene glycol-folic acid (PLGA-PEG-FA) nanoparticles containing 17-AAG were prepared and characterized. Cellular uptake and in vitro cytotoxicity of the prepared nanoparticles were determined in MCF-7 human breast cancer cells. The particle size of 17-AAG loaded folate targeted nanoparticles was 238.67±3.52 nm, drug loading was 8.25±2.49% and about 80% of drug was released from the nanoparticles over 10 days. Cellular uptake studies showed much higher intracellular uptake of folate targeted nanoparticle as compared to nontargeted nanoparticles. Cytotoxicity study showed 2 fold increase (P<0.05, n=3) in the cytotoxicity of folate targeted nanoparticle in comparison to free drug or nontargeted nanoparticles. Due to their targeting ability, nanometer size, high drug loading and controlled release behavior, 17-AAG loaded PLGA-PEG-FA nanoparticles might be developed as a targeted delivery system for breast and other cancer treatment.

Ibuprofen-phospholipid solid dispersions: improved dissolution and gastric tolerance.

Solid dispersions of ibuprofen with various phospholipids were prepared, and the effect of phospholipids on the in vitro dissolution and in vivo gastrointestinal toxicity of ibuprofen was evaluated. Most phospholipids improved the dissolution of ibuprofen; dimyristoylphosphatidyl-glycerol (DMPG) had the greatest effect. At 45 min, the extent of dissolution of ibuprofen from the ibuprofen-DMPG system (weight ratio 9:1) increased about 69% compared to ibuprofen alone; the initial rate of dissolution increased sevenfold. Increasing the DMPG content from 9:1 to 4:1 in this system did not significantly increase the rate and the extent of dissolution. X-ray diffraction and scanning electron micrograph indicated a smaller crystallite size of ibuprofen with fairly uniform distribution in the ibuprofen-DMPG solid dispersion. A small amount of carrier phospholipid significantly increases the rate and the extent of dissolution, which may increase the bioavailability of ibuprofen. The number of ulcers >0.5mm in size formed in the gastric mucosa of rats following ibuprofen, DMPG, DMPC and DPPC solid dispersions (ibuprofen and phospholipid weight ratio 4:1) were 8.6 ± 6.2, 3.9 ± 5.3, 5.3 ± 4.9 and 9.1 ± 7.4, respectively. Solid dispersion of ibuprofen with DMPG was significantly less irritating to the gastric mucosa than ibuprofen itself (one-way ANOVA, p<0.05). Solid dispersion of ibuprofen and DMPG decreases the gastric side effects of ibuprofen.

Zirconium phosphate nano-platelets: a novel platform for drug delivery in cancer therapy.

Doxorubicin was intercalated into novel zirconium phosphate nano-platelets (ZrP). The obtained doxorubicin intercalated ZrP nano-platelets had an impressive 34.9% (w/w) drug loading. We used this material to deliver doxorubicin to breast cancer cells (MCF-7). Cellular studies with MCF-7 cells showed higher uptake and cytotoxicity of doxorubicin loaded ZrP compared to free doxorubicin.