N-trimethyl chitosan coated nano-complexes enhance the oral bioavailability and chemotherapeutic effects of gemcitabine.

N-trimethyl chitosan (TMC) is a multifunctional polymer that can be used in various nanoparticle forms in the pharmaceutical, nutraceutical and biomedical fields. In this study, TMC was used as a mucoadhesive adjuvant to enhance the oral bioavailability and hence antitumour effects of gemcitabine formulated into nanocomplexes composed of poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) conjugated with d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). A central composite design was applied to achieve the optimal formulation. Cellular uptake and drug transportation studies revealed the nanocomplexes permeate over the intestinal cells via adsorptive-mediated and caveolae-mediated endocytosis. Pharmacokinetic studies demonstrated the oral drug bioavailability of the nanocomplexes was increased 5.1-fold compared with drug solution. In pharmacodynamic studies, the formulation reduced tumour size 3.1-fold compared with the drug solution. The data demonstrates that TMC modified nanocomplexes can enhance gemcitabine oral bioavailability and promote the anticancer efficacy.

A Review on Vitamin E Natural Analogues and on the Design of Synthetic Vitamin E Derivatives as Cytoprotective Agents.

Vitamin E, essential for human health, is widely used worldwide for therapeutic or dietary reasons. The differences in the metabolism and excretion of the multiple vitamin E forms are presented in this review. The important steps that influence the kinetics of each form and the distribution and processing of vitamin E forms by the liver are considered. The antioxidant as well as non-antioxidant properties of vitamin E forms are discussed. Finally, synthetic tocopherol and trolox derivatives, based on the design of multitarget directed compounds, are reviewed. It is demonstrated that selected derivatization of vitamin E or trolox structures can produce improved antioxidants, agents against cancer, cardiovascular and neurodegenerative disorders.

Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors.

Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring.

Synthesis of vitamin E and aliphatic lipid vanadium(IV) and (V) complexes, and their cytotoxic properties.

Novel vitamin E chelate derivatives and their VIV/V complexes have been synthesized and characterized, and their anticancer properties have been evaluated. The new complexes have been designed to exhibit enhanced cytotoxicity by combining high lipophilicity with the properties of vanadium to induce the formation of reactive oxygen species (ROS). In particular, the ß-tocopherol derivatives with iminodiethanol (ß-tocDEA) and dipicolylamine (ß-tocDPA) as well their VV and VIV complexes, [VVO(ß-tocDEA] and [VIVO(ß-tocDPA] have been synthesized and characterized by Nuclear Magnetic Resonance (NMR), Ultra Violet-Visible (UV-Vis) and Electron Paramagnetic Resonance (EPR) spectroscopies. Although the ß-tocopherol compounds exhibit antioxidant activity their complexes induce formation of radicals. In addition, two vanadium amphiphilic complexes of 2,2'-((2-hydroxyoctadecyl)azanediyl)bis(ethan-1-ol) (C18DEA) and 1-(bis(pyridin-2-ylmethyl)amino)octadecan-2-ol (C18DPA) known to activate O2 and produce ROS were synthesized and characterized (C. Drouza, A. Dieronitou, I. Hadjiadamou, M. Stylianou, J. Agric. Food. Chem., vol. 65, 2017, pp. 4942-4951). The four amphiphilic vanadium complexes exhibit enhanced hydrolytic stability. All compounds found to be cytotoxic for cancer cells exhibiting activity similar or higher to cis-platin.

Regulating intracellular ROS signal by a dual pH/reducing-responsive nanogels system promotes tumor cell apoptosis.

Purpose: The levels of reactive oxygen species (ROS) in tumor cells are much higher than that in normal cells, and rise rapidly under the influence of exogenous or endogenous inducing factors, eventually leading to the apoptosis of tumor cells. Therefore, this study prepared a dual pH/reducing-responsive poly (N-isopropylacrylamide-co-Cinnamaldehyde-co-D-α-tocopheryl polyethylene glycol 1000 succinate, PssNCT) nanogels, which employed two exogenous ROS inducers, cinnamaldehyde (CA) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), to selectively induce apoptosis by regulating ROS levels in tumor cells. Methods: The PssNCT nanogels were prepared by the free radical precipitation polymerization under the crosslink between pH-sensitive hydrazone and reducing-sensitive disulfide bonds, followed by the physicochemical and morphological characteristics investigations. Plasma stability, dual pH/reducing responsive degradation and in vitro release were also assessed. In cell experiments, cytotoxicity in different cells were first detected. The intracellular ROS levels and mitochondrial functions of tumor cells were then evaluated. Moreover, the apoptosis and western-blot assays were employed to verify the association between ROS levels elevation and apoptosis in tumor cells. Results: The nanogels exhibited a round-like hollow structure with the diameter smaller than 200nm. The nanogels were stable in plasma, while showed rapid degradation in acidic and reducing environments, thus achieving significant release of CA and TPGS in these media. Furthermore, the sufficient amplification of ROS signals was induced by the synergistically function of CA and TPGS on mitochondria, which resulted in the opening of the mitochondrial apoptotic pathway and enhanced cytotoxicity on MCF-7 cells. However, nanogels barely affected L929 cells owing to their lower intracellular ROS basal levels. Conclusion: The specific ROS regulation method achieved by these nanogels could be explored to selectively kill tumor cells according to the difference of ROS signals in different kinds of cells.

Preparation of Peppermint Oil-Based Nanodevices Loaded with Paclitaxel: Cytotoxic and Apoptosis Studies in HeLa Cells.

In this work, several normal, oil-in-water (o/w) microemulsions (MEs) were prepared using peppermint essential oil, jojoba oil, trans-anethole, and vitamin E as oil phases to test their capacity to load paclitaxel (PTX). Initially, pseudo-ternary partial phase diagrams were constructed in order to find the normal microemulsion region using d-α-tocopherol polyethylene glycol 1000 succinate (TPGS-1000) as surfactant and isobutanol (iso-BuOH) as co-surfactant. Selected ME formulations were loaded with PTX reaching concentrations of 0.6 mg mL-1 for the peppermint oil and trans-anethole MEs, while for the vitamin E and jojoba oil MEs, the maximum concentration was 0.3 mg mL-1. The PTX-loaded MEs were stable according to the results of heating-cooling cycles and mechanical force (centrifugation) test. Particularly, drug release profile for the PTX-loaded peppermint oil ME (MEPP) showed that ∼ 90% of drug was released in the first 48 h. Also, MEPP formulation showed 70% and 90% viability reduction on human cervical cancer (HeLa) cells after 24 and 48 h of exposure, respectively. In addition, HeLa cell apoptosis was confirmed by measuring caspase activity and DNA fragmentation. Results showed that the MEPP sample presented a major pro-apoptotic capability by comparing with the unloaded PTX ME sample.

Characterization, optimization, and in vitro evaluation of Technetium-99m-labeled niosomes.

BACKGROUND AND PURPOSE: Niosomes are nonionic surfactant-based vesicles that exhibit certain unique features which make them favorable nanocarriers for sustained drug delivery in cancer therapy. Biodistribution studies are critical in assessing if a nanocarrier system has preferential accumulation in a tumor by enhanced permeability and retention effect. Radiolabeling of nanocarriers with radioisotopes such as Technetium-99m (99mTc) will allow for the tracking of the nanocarrier noninvasively via nuclear imaging. The purpose of this study was to formulate, characterize, and optimize 99mTc-labeled niosomes. METHODS: Niosomes were prepared from a mixture of sorbitan monostearate 60, cholesterol, and synthesized D-α-tocopherol polyethylene glycol 1000 succinate-diethylenetriaminepentaacetic acid (synthesis confirmed by 1H and 13C nuclear magnetic resonance spectroscopy). Niosomes were radiolabeled by surface chelation with reduced 99mTc. Parameters affecting the radiolabeling efficiency such as concentration of stannous chloride (SnCl2·H2O), pH, and incubation time were evaluated. In vitro stability of radiolabeled niosomes was studied in 0.9% saline and human serum at 37°C for up to 8 hours. RESULTS: Niosomes had an average particle size of 110.2±0.7 nm, polydispersity index of 0.229±0.008, and zeta potential of -64.8±1.2 mV. Experimental data revealed that 30 µg/mL of SnCl2·H2O was the optimal concentration of reducing agent required for the radiolabeling process. The pH and incubation time required to obtain high radiolabeling efficiency was pH 5 and 15 minutes, respectively. 99mTc-labeled niosomes exhibited high radiolabeling efficiency (>90%) and showed good in vitro stability for up to 8 hours. CONCLUSION: To our knowledge, this is the first study published on the surface chelation of niosomes with 99mTc. The formulated 99mTc-labeled niosomes possessed high radiolabeling efficacy, good stability in vitro, and show good promise for potential use in nuclear imaging in the future.

Testosterone- and vitamin-grafted cellulose ethers for sustained release of camptothecin.

Camptothecin (CPT), a potent anticancer drug with known antiviral activity, is halted of clinical use. Few drug delivery systems of CPT are approved for therapy. Hereby, we propose the encapsulation of hydrophobic CPT in the inner core of cellulose nanoaggregates for sustained release with retaining of antiproliferative activity. Cellulose conjugates were synthesized by esterification of methyl cellulose, hydroxyethyl cellulose and (hydroxypropyl)methyl cellulose with testosterone, ergocalciferol and dl-α-tocopherol hemisuccinates. The degree of substitution attained ranged from 0.004 to 0.025 and no depolymerization was observed by size exclusion chromatography. ATR-FTIR and NMR spectroscopies confirmed grafting of testosterone and vitamins to celluloses. According to dynamic light scattering, it resulted in their self-assembly in aqueous medium as stable and slightly negatively charged nanoaggregates of 213 to 731 nm. Nanoaggregates formation was also assessed using transmission electron and atomic force microscopies. CPT was encapsulated in the cellulose nanoaggregates, achieving a content of 1.7-13.0 wt %. Sustained release of camptothecin over 150 h was observed in simulated physiological conditions. CPT-loaded cellulose nanoparticles appeared to be possible candidates for chemotherapy, according to observed cytotoxicity against MCF-7 cancer cells.

Redox-responsive F127-folate/F127-disulfide bond-d-α-tocopheryl polyethylene glycol 1000 succinate/P123 mixed micelles loaded with paclitaxel for the reversal of multidrug resistance in tumors.

INTRODUCTION: The development of nanodrug carriers utilizing tumor microenvironment has become a hotspot in reversing multidrug resistance (MDR). MATERIALS AND METHODS: This study synthesized a redox-sensitive copolymer, Pluronic F127-disulfide bond-d-α-tocopheryl polyethylene glycol 1000 succinate (FSST), through the connection of the reduction-sensitive disulfide bond between F127 and d-α-tocopheryl polyethylene glycol 1000 succinate. This polymer could induce the elevation of reactive oxygen species (ROS) levels, ultimately resulting in cytotoxicity. Moreover, the redox-responsive mixed micelles, F127-folate (FA)/FSST/P123 (FFSSTP), based on FSST, Pluronic F127-FA, and Pluronic P123, were prepared to load paclitaxel (PTX). RESULTS: The in vitro release study demonstrated that FFSSTP/PTX accelerated the PTX release through the breakage of disulfide bond in reductive environment. In cellular experiment, FFSSTP/PTX induced significant apoptosis in PTX-resistant MCF-7/PTX cells through inhibiting adenosine triphosphate (ATP)-binding cassette proteins from pumping out PTX by interfering with the mitochondrial function and ATP synthesis. Furthermore, FFSSTP/PTX induced apoptosis through elevating the intracellular levels of ROS. CONCLUSION: FFSSTP could become a potential carrier for the treatment of MDR tumors.

Transferrin and tocopheryl-polyethylene glycol-succinate dual ligands decorated, cisplatin loaded nano-sized system for the treatment of lung cancer.

Nanocarriers decorated with different ligands were used to achieve lung cancer treatment. Surface decoration of nanoparticulate system will assist in targeting the drug to specific tumor cells and tissues. The aim of this research was to develop a dual ligands decorated nanocarriers (NCs), which could increase the cell uptake and anti-tumor efficiency. Two different ligands: Transferrin (Tf) and D-α-tocopheryl polyethylene glycol succinate (TPGS) containing ligands were synthesized. Dual ligands decorated nanocarriers (DL-NCs) was constructed. The in vitro cytotoxicity, in vivo biodistribution, and in vivo antitumor efficacy of the DL-NCs were evaluated. DL-NCs can efficiently deliver cisplatin (CDDP) into lung cancer cells in vitro and reduced xenograft tumor size in vivo. The encapsulation of CDDP in the DL-NCs significantly improved the cytotoxicity and antitumor efficacy. DL-NCs held great potential for achieving an optimal therapeutic effect in the treatment of lung cancer.

Vitamin E succinate-conjugated F68 micelles for mitoxantrone delivery in enhancing anticancer activity.

Mitoxantrone (MIT) is a chemotherapeutic agent with promising anticancer efficacy. In this study, Pluronic F68-vitamine E succinate (F68-VES) amphiphilic polymer micelles were developed for delivering MIT and enhancing its anticancer activity. MIT-loaded F68-VES (F68-VES/MIT) micelles were prepared via the solvent evaporation method with self-assembly under aqueous conditions. F68-VES/MIT micelles were found to be of optimal particle size with the narrow size distribution. Transmission electron microscopy images of F68-VES/MIT micelles showed homogeneous spherical shapes and smooth surfaces. F68-VES micelles had a low critical micelle concentration value of 3.311 mg/L, as well as high encapsulation efficiency and drug loading. Moreover, F68-VES/MIT micelles were stable in the presence of fetal bovine serum for 24 hours and maintained sustained drug release in vitro. Remarkably, the half maximal inhibitory concentration (IC50) value of F68-VES/MIT micelles was lower than that of free MIT in both MDA-MB-231 and MCF-7 cells (two human breast cancer cell lines). In addition, compared with free MIT, there was an increased trend of apoptosis and cellular uptake of F68-VES/MIT micelles in MDA-MB-231 cells. Taken together, these results indicated that F68-VES polymer micelles were able to effectively deliver MIT and largely improve its potency in cancer therapy.

Synthesis of the vitamin E amino acid esters with an enhanced anticancer activity and in silico screening for new antineoplastic drugs.

Tocopherols and tocotrienols belong to the family of vitamin E (VE) with the well-known antioxidant properties. For certain α-tocopherol and γ-tocotrienol derivatives used as the lead compounds in this study, antitumor activities against various cancer cell types have been reported. In the course of the last decade, structural analogs of VE (esters, ethers and amides) with an enhanced antiproliferative and proapoptotic activity against various cancer cells were synthesized. Within the framework of this study, seven amino acid esters of α-tocopherol (4a-d) and γ-tocotrienol (6a-c) were prepared using the EDC/DMAP reaction conditions and their ability to inhibit proliferation of the MCF-7 and MDA-MB-231 breast cancer cells and the A549 lung cancer cells was evaluated. Compound 6a showed an activity against all three cell lines (IC50: 20.6µM, 28.6µM and 19µM for the MCF-7, MDA-MB-231 and A549 cells, respectively), while compound 4a inhibited proliferation of the MCF-7 (IC50=8.6µM) and A549 cells (IC50=8.6µM). Ester 4d exerted strong antiproliferative activity against the estrogen-unresponsive, multi-drug resistant MDA-MB-231 breast cancer cell line, with IC50 value of 9.2µM. Compared with the strong activity of compounds 4a, 4d and 6a, commercial α-tocopheryl succinate and γ-tocotrienol showed only a limited activity against all three cell lines, with IC50 values >50µM. Investigation of the cell cycle phase distribution and the cell death induction confirmed an apoptosis of the MDA-MB-231 cells treated with 4d, as well as a synergistic effect of 4d with the known anticancer drug doxorubicin. This result suggests a possibility of a combined therapy of breast cancer in order to improve the therapeutic response and to lower the toxicity associated with a high dose of doxorubicin. The stability study of 4d in human plasma showed that ca. 83% initial concentration of this compound remains in plasma in the course of six hours incubation. The ligand based virtual screening of the ChEMBL database identified new compounds with a potential antiproliferative activity on MCF-7 and on multi-drug resistant MDA-MB 231 breast cancer cells.

PEGylated γ-tocotrienol isomer of vitamin E: Synthesis, characterization, in vitro cytotoxicity, and oral bioavailability.

Vitamin E refers to a family of eight isomers divided into two subgroups, tocopherols and the therapeutically active tocotrienols (T3). The PEGylated α-tocopherol isomer of vitamin E (vitamin E TPGS) has been extensively investigated for its solubilizing capacity as a nonionic surfactant in various drug delivery systems. Limited information, however, is available about the PEG conjugates of the tocotrienol isomers of vitamin E. In this study two PEGylated γ-T3 variants with mPEG molecular weights of 350 (γ-T3PGS 350) and 1000 (γ-T3PGS 1000) were synthesized by a two-step reaction procedure and characterized by (1)H NMR, HPLC, and mass spectroscopy. The physical properties of their self-assemblies in water were characterized by zeta, CMC, and size analysis. Similar physical properties were found between the PEGylated T3 and vitamin E TPGS. PEGylated T3 were also found to retain the in vitro cytotoxic activity of the free T3 against the MCF-7 and the triple-negative MDA-MB-231 breast cancer cells. PEGylated γ-T3 also increased the oral bioavailability of γ-T3 by threefolds when compared to the bioavailability of γ-T3 formulated into a self-emulsified drug delivery system. No significant differences in biological activity were found between the PEG 350 and 100 conjugates. Results from this study suggest that PEGylation of γ-T3 represents a viable platform for the oral and parenteral delivery of γ-T3 for potential use in the prevention of breast cancer.

Anticancer and antiangiogenic activity of surfactant-free nanoparticles based on self-assembled polymeric derivatives of vitamin E: structure-activity relationship.

α-Tocopheryl succinate (α-TOS) is a well-known mitochondrially targeted anticancer compound, however, it is highly hydrophobic and toxic. In order to improve its activity and reduce its toxicity, new surfactant-free biologically active nanoparticles (NP) were synthesized. A methacrylic derivative of α-TOS (MTOS) was prepared and incorporated in amphiphilic pseudoblock copolymers when copolymerized with N-vinylpyrrolidone (VP) by free radical polymerization (poly(VP-co-MTOS)). The selected poly(VP-co-MTOS) copolymers formed surfactant-free NP by nanoprecipitation with sizes between 96 and 220 nm and narrow size distribution, and the in vitro biological activity was tested. In order to understand the structure-activity relationship three other methacrylic monomers were synthesized and characterized: MVE did not have the succinate group, SPHY did not have the chromanol ring, and MPHY did not have both the succinate group and the chromanol ring. The corresponding families of copolymers (poly(VP-co-MVE), poly(VP-co-SPHY), and poly(VP-co-MPHY)) were synthesized and characterized, and their biological activity was compared to poly(VP-co-MTOS). Both poly(VP-co-MTOS) and poly(VP-co-MVE) presented triple action: reduced cell viability of cancer cells with little or no harm to normal cells (anticancer), reduced viability of proliferating endothelial cells with little or no harm to quiescent endothelial cells (antiangiogenic), and efficiently encapsulated hydrophobic molecules (nanocarrier). The anticancer and antiangiogenic activity of the synthesized copolymers is demonstrated as the active compound (vitamin E or α-tocopheryl succinate) do not need to be cleaved to trigger the biological action targeting ubiquinone binding sites of complex II. Poly(VP-co-SPHY) and poly(VP-co-MPHY) also formed surfactant-free NP that were also endocyted by the assayed cells; however, these NP did not selectively reduce cell viability of cancer cells. Therefore, the chromanol ring of the vitamin E analogues has an important role in the biological activity of the copolymers. Moreover, when succinate moiety is substituted and vitamin E is directly linked to the macromolecular chain through an ester bond, the biological activity is maintained.

Synthesis and properties of vitamin E analog-conjugated neomycin for delivery of RNAi drugs to liver cells.

RNA interference (RNAi) is a promising tool to regulate gene expression by external double stranded RNAs (dsRNAs) such as siRNAs. As an efficient method to deliver siRNAs to liver cells, we propose a novel strategy using vitamin E (VE)-conjugated neomycin derivatives. With the aim of delivering RNAi-based drugs to liver cells, several tripod-type and prodrug-type neomycin derivatives were synthesized, all of which were thermodynamically stabilized RNA duplexes. The prodrug-type derivative 7 and the tripod-type derivative 10 were delivered to liver cancer cells and successfully induced RNAi activity. These results indicated the potential use of natural aminoglycosides as carriers of RNAi drugs.

Fmoc-conjugated PEG-vitamin E2 micelles for tumor-targeted delivery of paclitaxel: enhanced drug-carrier interaction and loading capacity.

The purpose of this study is to develop an improved drug delivery system for enhanced paclitaxel (PTX) loading capacity and formulation stability based on PEG5K-(vitamin E)2 (PEG5K-VE2) system. PEG5K-(fluorenylmethoxycarbonyl)-(vitamin E)2 (PEG5K-FVE2) was synthesized using lysine as the scaffold. PTX-loaded PEG5K-FVE2 micelles were prepared and characterized. Fluorescence intensity of Fmoc in the micelles was measured as an indicator of drug-carrier interaction. Cytotoxicity of the micelle formulations was tested on various tumor cell lines. The therapeutic efficacy and toxicity of PTX-loaded micelles were investigated using a syngeneic mouse model of breast cancer (4T1.2). Our data suggest that the PEG5K-FVE2 micelles have a low CMC value of 4 µg/mL and small sizes (~60 nm). The PTX loading capacity of PEG5K-FVE2 micelles was much higher than that of PEG5K-VE2 micelles. The Fmoc/PTX physical interaction was clearly demonstrated by a fluorescence quenching assay. PTX-loaded PEG5K-FVE2 micelles exerted more potent cytotoxicity than free PTX or Taxol formulation in vitro. Finally, intravenous injection of PTX-loaded PEG5K-FVE2 micelles showed superior anticancer activity compared with PEG5K-VE2 formulation with minimal toxicity in a mouse model of breast cancer. In summary, incorporation of a drug-interactive motif (Fmoc) into PEG5K-VE2 micelles represents an effective strategy to improve the micelle formulation for the delivery of PTX.

Dendrimer-TPGS mixed micelles for enhanced solubility and cellular toxicity of taxanes.

Taxanes are the most effective, efficient and broad spectrum anticancer drugs for the treatment of various cancers. However, poor aqueous solubility is the major problem in their delivery at higher concentrations in cancer cells. In this research work, poor solubility of taxanes is addressed by preparing dendrimer and d-α-tocopherol polyethylene glycol succinate (TPGS) mixed micelles by taking into consideration the advantages of TPGS such as solubility enhancement and P-glycoprotein inhibition. Dendrimer-TPGS mixed micelles were prepared by solvent casting method. Docetaxel (DTX) and paclitaxel (PTX) were chosen as model drugs representing the group of taxanes. Nanomicelles were characterized by DLS, FTIR, PXRD, in vitro drug release and hemolytic studies. Effects of pH and dendrimer to TPGS ratio on the solubility of taxanes were also studied. Solubility of DTX and PTX were increased by 20.36 and 34.95 folds, respectively, when formulated in dendrimer-TPGS mixed micelles. Drug release studies exhibited better release profile of encapsulated drug at acidic pH which is advantageous in enhanced intracellular drug release in cancer cells. Formulations were found to be biocompatible in hemolytic toxicity assay. Cytotoxicity studies revealed that anticancer activities of both drugs were enhanced after encapsulation in micelles against cancer cells while caused very low toxicity to normal cells. Thus, dendrimer-TPGS mixed micelles are promising alternate for delivery of poorly water-soluble drugs taxanes.

The reduction of anti-cancer drug antagonism by the spatial protection of drugs with PLA-TPGS nanoparticles.

Docetaxel (DCL) and tamoxifen (TAM) individually are potent drugs in the fight against breast cancer. However when used in combination, they become antagonistic because of differential metabolism of both drugs. We reasoned that by spatially protecting them from metabolizing enzymes with poly (lactide)-D-α-tocopheryl polyethylene glycol succinate (PLA-TPGS) nanoparticles (NPs), we might reduce this drug antagonism. We now report that the drug antagonism between DCL and TAM in MCF7 cell line, was significantly reduced when co-delivered in PLA-TPGS NPs. In addition, this effect of NPs attenuated at high drug concentrations. To investigate the role of NPs in the reduction of drug antagonism, we quantified cellular uptake of the fluorescent model drug coumarin 6 (C6) encapsulated in a rigorous permutation of drugs-nanoparticles ratios. NPs carrying C6 exhibited enhanced cellular uptake over their free C6 counterparts at correspondingly low drug concentrations. This led us to conclude that the reduction of drug antagonism by NPs is correlated to cellular uptake and being in NPs therefore protects both drugs until they are released intracellular for therapeutic anti-cancer effect.

Docetaxel-loaded nanoparticles based on star-shaped mannitol-core PLGA-TPGS diblock copolymer for breast cancer therapy.

A star-shaped biodegradable polymer, mannitol-core poly(d,l-lactide-co-glycolide)-d-α-tocopheryl polyethylene glycol 1000 succinate (M-PLGA-TPGS), was synthesized in order to provide a novel nanoformulation for breast cancer chemotherapy. This novel copolymer was prepared by a core-first approach via three stages of chemical reaction, and was characterized by nuclear magnetic resonance, gel permeation chromatography and thermogravimetric analysis. The docetaxel-loaded M-PLGA-TPGS nanoparticles (NPs), prepared by a modified nanoprecipitation method, were observed to be near-spherical shape with narrow size distribution. Confocal laser scanning microscopy showed that the uptake level of M-PLGA-TPGS NPs was higher than that of PLGA NPs and PLGA-TPGS NPs in MCF-7 cells. A significantly higher level of cytotoxicity was achieved with docetaxel-loaded M-PLGA-TPGS NPs than with commercial Taxotere®, docetaxel-loaded PLGA-TPGS and PLGA NPs. Examination of the drug loading and encapsulation efficiency proved that star-shaped M-PLGA-TPGS could carry higher levels of drug than linear polymer. The in vivo experiment showed docetaxel-loaded M-PLGA-TPGS NPs to have the highest anti-tumor efficacy. In conclusion, the star-like M-PLGA-TPGS copolymer shows potential as a promising drug-loaded biomaterial that can be applied in developing novel nanoformulations for breast cancer therapy.

Relação vitamina E: vitamina C sobre a qualidade da carne de frangos submetidos ao estresse pré-abate / Vitamin E: vitamin C relationship on meat quality of broiler chicken submitted to pre-slaughter stress

Determinou-se a melhor relação vitamina E:vitamina C em dietas para frangos de corte, visando ao melhor desempenho produtivo e à melhor qualidade da carne das aves submetidas ao estresse pré-abate. Utilizaram-se 800 pintos de corte, machos, distribuídos em delineamento inteiramente ao acaso, em esquema fatorial 2x4, com dois níveis de suplementação de vitamina E - 0 e 250mg/kg - e quatro de vitamina C - 0, 150, 300 e 450mg/kg. Aos 42 dias de idade, 12 horas ante mortem, amostras de aves de cada tratamento foram submetidas ao estresse por calor e, em seguida, pelo transporte. Foram avaliadas características de desempenho - peso vivo, consumo de ração e conversão alimentar - , bem como rendimento de carcaça e qualidade da carne de peito e coxas - perda de água, cor e pH. Os níveis de vitaminas avaliadas não influenciaram nas características de desempenho avaliadas. Houve menor rendimento de peito (34,2 vs. 34,9%) e maior pH inicial (6,3 vs. 6,1) dos cortes, para aves que sofreram estresse em relação àquelas que não foram submetidas ao estresse pré-abate.

The best relationship for vitamin E:vitamin C in diets for broilers regarding growth performance and meat quality of birds submitted to pre-slaughter stress was determined. 800 male chicks at one day of age were distributed in a completely randomized design in a 2x4 factorial scheme, with two levels of vitamin E supplementation - 0 and 250mg/kg - and four of vitamin C - 0, 150, 300 and 450mg/kg. At 42 days of age, 12 hours ante-mortem, samples of birds from each treatment were submitted to heat stress and then transportation. The performance characteristics evaluated were body weight, feed intake and feed:gain ratio, carcass yield and meat quality of breast and thighs, water loss, color and pH. The levels of vitamins evaluated did not influence the performance characteristics measured. There was a lower breast yield (34.2 vs 34.9%) and higher initial pH (6.3 vs 6.1) in the cuts for birds that suffered stress than for those who did not undergo pre-slaughter stress.