Α-tocopheryl Polyethylene Glycol Succinate Research Articles

Reduction-sensitive shell crosslinked TPGS micelles: Formulation and colloidal characterizations

This study reports stabilization of α-tocopheryl polyethylene glycol succinate (TPGS) micelles by crosslinking their shell. This was accomplished by derivatizing terminal alcohol of the surfactant into aldehydes which were later linked with cystamine. Crosslinking of headgroups occurred through bridging of aldehyde termini with cystamine. Disulfide bonds offered redox sensitivity to the crosslinked micelles. Successful derivatization of the surfactant has been demonstrated through Fourier-transformed infrared spectroscopic and nuclear magnetic resonance data. Micelles were characterized by dynamic light scattering, neutron scattering, electron microscopic and fluorimetric techniques. We observed that, in spite of more than two-fold increase in size, micelles retained their core-shell spherical structure after shell crosslinking. Crosslinked micelles exhibited superior dilution stability in phosphate buffer. De-crosslinking indeed occurred under reductive condition and at low pH. This, however, did not cause complete dissociation of micelles implying that association among TPGS molecules was not affected during de-crosslinking. Based on these observations, we suggest that the release of payloads from crosslinked TPGS micelles can be triggered in reductive and low pH environment while avoiding the premature release.

Validation of Knock-Out Caco-2 TC7 Cells as Models of Enterocytes of Patients with Familial Genetic Hypobetalipoproteinemias

Abetalipoproteinemia (FHBL-SD1) and chylomicron retention disease (FHBL-SD3) are rare recessive disorders of lipoprotein metabolism due to mutations in MTTP and SAR1B genes, respectively, which lead to defective chylomicron formation and secretion. This results in lipid and fat-soluble vitamin malabsorption, which induces severe neuro-ophthalmic complications. Currently, treatment combines a low-fat diet with high-dose vitamin A and E supplementation but still fails in normalizing serum vitamin E levels and providing complete ophthalmic protection. To explore these persistent complications, we developed two knock-out cell models of FHBL-SD1 and FHBL-SD3 using the CRISPR/Cas9 technique in Caco-2/TC7 cells. DNA sequencing, RNA quantification and Western blotting confirmed the introduction of mutations with protein knock-out in four clones associated with i) impaired lipid droplet formation and ii) defective triglyceride (-57.0 ± 2.6% to -83.9 ± 1.6%) and cholesterol (-35.3 ± 4.4% to -60.6 ± 3.5%) secretion. A significant decrease in α-tocopherol secretion was also observed in these clones (-41.5 ± 3.7% to -97.2 ± 2.8%), even with the pharmaceutical forms of vitamin E: tocopherol-acetate and tocofersolan (α-tocopheryl polyethylene glycol succinate 1000). MTTP silencing led to a more severe phenotype than SAR1B silencing, which is consistent with clinical observations. Our cellular models thus provide an efficient tool to experiment with therapeutic strategies and will allow progress in understanding the mechanisms involved in lipid metabolism.

Water driven transformation of a nonionic microemulsion into liquid crystalline phase: Structural characterizations and drug release behavior

This study reports structural characterization of liquid crystalline (LC) phase, formed through water driven transition in a nonionic microemulsion (ME). ME was formulated with α-tocopheryl polyethylene glycol succinate (TPGS) – Span 80 (3:1) as surfactant mixture and Captex 355 (a medium chain triglyceride) as oil phase. The role of surfactant mixture was elucidated by small angle neutron scattering (SANS) experiments. SANS analyses revealed that, at a specific ratio, TPGS micelles and Span 80 vesicles interacted to form ellipsoidal nanostructures. The ME transformed to LC phase during progressive water addition. Subsequent structural changes were investigated by polarized light microscopy, differential scanning calorimetry, texture profile and rheological analyses. Transition occurred with 19–24% water addition and it was accompanied with; (a) change of isotropic ME to birefringent LC phase, and (b) improvement in the rheological properties. Interestingly, the transition downshifted to 9.8% water level upon loading the oil phase with 20 mg/ml paclitaxel (PLX). LC structures remained stable at physiological temperature up to 72 h and offered controlled release of PLX under artificial sink conditions. We suggest that in situ development of LC phase can be explored to create long-residing intra-muscular depot formulations.

Top-Down Synthesis of a Lamivudine-Zidovudine Nano Co-Crystal

Lamivudine (3TC) and zidovudine (AZT) are antiretroviral agents used to manage HIV/AIDS infection. A wet media milling top-down approach was used to develop and produce nano co-crystals of 3TC and AZT. Micro co-crystals were prepared by solvent evaporation and subsequently milled in the presence of two surfactants, viz., sodium lauryl sulfate (SLS) and α-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000). Optimisation was undertaken using design of experiments (DoE) and response surface methodology (RSM) to establish and identify parameters that may affect the manufacturing of nano co-crystals. The impact of SLS and TPGS 1000 concentration, milling time, and number of units of milling medium on the manufacturing of nano co-crystals, was investigated. The critical quality attributes (CQA) monitored were particle size (PS), Zeta potential (ZP), and polydispersity index (PDI). Powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, transmission electron microscopy, energy dispersive X-ray spectroscopy scanning electron microscopy, and cytotoxicity assays were used for additional characterization of the optimised nano co-crystal. The mean PS, PDI, and ZP of the optimised top-down nanocrystal were 271.0 ± 92.0 nm, 0.467 ± 0.073, and −41.9 ± 3.94 mV, respectively. In conclusion, a simple, inexpensive, rapid, and precise method of nano co-crystal manufacturing was developed, validated, and optimised using DoE and RSM, and the final product exhibited the target CQA.

TPGS/hyaluronic acid dual-functionalized PLGA nanoparticles delivered through dissolving microneedles for markedly improved chemo-photothermal combined therapy of superficial tumor

Nanoparticles (NPs) have shown potential in cancer therapy, while a single administration conferring a satisfactory outcome is still unavailable. To address this issue, the dissolving microneedles (DMNs) were developed to locally deliver functionalized NPs with combined chemotherapy and photothermal therapy (PTT). α-Tocopheryl polyethylene glycol succinate (TPGS)/hyaluronic acid (HA) dual-functionalized PLGA NPs (HD10 NPs) were fabricated to co-load paclitaxel and indocyanine green. HD10 NPs significantly enhanced the cytotoxicity of low-dose paclitaxel because of active and mitochondrial targeting by HA and TPGS, respectively. PTT could further sensitize tumor cells toward chemotherapy by promoting apoptosis into the advanced period, highly activating caspase 3 enzyme, and significantly reducing the expression of survivin and MMP-9 proteins. Further, the anti-tumor effects of HD10 NPs delivered through different administration routes were conducted on the 4T1 tumor-bearing mice. After a single administration, HD10 NPs delivered with DMNs showed the best anti-tumor effect when giving chemotherapy alone. As expected, the anti-tumor effect was profoundly enhanced after combined therapy, and complete tumor ablation was achieved in the mice treated with DMNs and intra-tumor injection. Moreover, DMNs showed better safety due to moderate hyperthermia. Therefore, the DMNs along with combined chemo-photothermal therapy provide a viable treatment option for superficial tumors.

Synthesis, Colloidal Characterization and Targetability of Phenylboronic Acid Functionalized α-Tocopheryl Polyethylene Glycol Succinate in Cancer Cells.

This study reports targetable micelles developed after covalent functionalization of α-tocopheryl polyethylene glycol succinate (TPGS) with amino phenylboronic acid (APBA). Nuclear magnetic resonance (NMR) and infrared (IR) spectroscopic results showed successful attachment of APBA to the hydrophilic segment of TPGS. Dynamic light scattering and small-angle neutron scattering studies revealed that the conjugate self-assembled in water to produce spherical core-shell micelles (14–20 nm) which remained stable against temperature (ca. 25–45 °C) and pH changes. The micelles could solubilize a high payload of paclitaxel (PLX) without exhibiting changes in the average size. However, at the saturation solubility, drug molecules migrated from the core to the shell region and engaged with APBA groups via π–π stacking interaction. Confocal microscopy and cell sorting analyses verified the effective translocation ability of TPGS-APBA micelles in sialic acid (SA) expressing MDA-MB-453 cells. At equivalent PLX dose, TPGS-APBA micelles showed about a twofold improvement in apoptotic death among the cells exposed for 2 h. Our findings indicate that the attachment of APBA can be a potential strategy for improving the intra-cellular localization of carriers among cancer cells expressing SA residues.

Quality by Design Optimization of Cold Sonochemical Synthesis of Zidovudine-Lamivudine Nanosuspensions.

Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used to manage HIV/AIDS infection. The compounds require frequent dosing, exhibit unpredictable bioavailability and a side effect profile that includes hepato- and haema-toxicity. A novel pseudo one-solvent bottom-up approach and Design of Experiments using sodium dodecyl sulphate (SDS) and α-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000) to electrosterically stablize the nano co-crystals was used to develop, produce and optimize 3TC and AZT nano co-crystals. Equimolar solutions of 3TC in surfactant dissolved in de-ionised water and AZT in methanol were rapidly injected into a vessel and sonicated at 4 °C. The resultant suspensions were characterized using a Zetasizer and the particle size, polydispersity index and Zeta potential determined. Optimization of the nanosuspensions was conducted using a Central Composite Design to produce nano co-crystals with specific identified and desirable Critical Quality Attributes including particle size (PS) < 1000 nm, polydispersity index (PDI) < 0.500 and Zeta potential (ZP) < −30mV. Further characterization was undertaken using Fourier Transform infrared spectroscopy, energy dispersive X-ray spectroscopy, differential scanning calorimetry, powder X-ray diffraction and transmission electron microscopy. In vitro cytotoxicity studies revealed that the optimized nano co-crystals reduced the toxicity of AZT and 3TC to HeLa cells.

Iron Transport Tocopheryl Polyethylene Glycol Succinate in Animal Health and Diseases.

Gut health is the starting place for maintaining the overall health of an animal. Strategies to maintain gut health are, thus, an important part in achieving the goal of improving animal health. A new strategy to do this involves two molecules: the iron transport protein ovotransferrin (IT) and α-tocopheryl polyethylene glycol succinate (TPGS), which result in the novel formulation of ITPGS. These molecules help reduce gut pathogens, while enhancing the absorption and bioavailability of therapeutic drugs, phytomedicines, and nanomedicines. This, in turn, helps to maintain normal health in animals. Maintaining the gastrointestinal tract (GIT) in its normal condition is key for successful absorption and efficacy of any nutrient. A compromised GIT, due to an imbalance (dysbiosis) in the GIT microbiome, can lead to an impaired GI barrier system with impaired absorption and overall health of the animal. The molecules in ITPGS may address the issue of poor absorption by keeping the GI system healthy by maintaining the normal microbiome and improving the absorption of nutrients through multiple mechanisms involving antioxidative, anti-inflammatory, immunomodulatory, and antimicrobial activities. The ITPGS technology can allow the dose of active pharmaceutical or herbal medicine to be significantly reduced in order to attain equal or better efficacy. With complimentary actions between IT and TPGS, ITPGS presents a novel approach to increase the bioavailability of drugs, phytoconstituents, nutrients, and nanomedicines by enhanced transport to the tissues at the site of action, while reducing gut pathogen load. The ITPGS approach appears to be a novel strategy for maintaining the health of animals by manipulation of microbiota.

Rhodamine-loaded, cross-linked, carboxymethyl cellulose sodium-coated super-paramagnetic iron oxide nanoparticles: Development and in vitro localization study for magnetic drug-targeting applications

Abstract A facile, one-pot, room-temperature synthesis method for super-paramagnetic iron oxide nanoparticles (SPIONs) employing simple reactants was attempted using a battery of stabilizers possessing either hydroxyl (methyl cellulose, polyethylene glycol), or a combination of hydroxyl and carboxyl functional groups (carboxymethyl cellulose sodium, trisodium citrate, α-tocopheryl polyethylene glycol succinate), from carbohydrate and non-carbohydrate sources, added to the reaction mixture in situ. Finally, carboxymethyl cellulose sodium (CMC)-coated SPIONs were selected, which were further cross-linked with epichlorohydrin to improve the stability of coating and load a water-soluble model molecule, rhodamine B. The selected formulation with optimum nanometric size (24 ± 8 nm) was characterized for morphology, surface charge, interaction of CMC with iron oxide, crystal phase, magnetization properties and finally microfluidic studies were carried out on the optimized formulation to determine the in vitro SPIONs localization pattern in the presence of an external magnetic field (150 mT) in a simulated glass capillary to demonstrate its targeting potential. A biconvex pattern of aggregation was observed when observed for time, t = 0–100 s with the rate of localization decreasing as a function of time. The study was used to standardize CMC as a standard capping agent for the formulation of SPIONs, which have potential for numerous bio-medical applications, and to load rhodamine B as a water-soluble model molecule.

Adsorption behavior of α-tocopheryl succinate and α-tocopheryl polyethylene glycol succinate onto weakly basic anion exchange resins

Polyethylene glycol (PEG) esters are important, nontoxic and biodegradable non-ionic surfactants. A key procedure in producing PEG esters is their separation from unreacted or excess acids. We propose an adsorption method using the weakly basic anion exchange resins for the separation of organic acids and PEG esters for the first time. With α-tocopheryl polyethylene glycol succinate (TPGS) and α-tocopheryl succinate (α-TS) as the examples of PEG ester and organic acid, respectively, single-component equilibrium experiments revealed the great potential of this method. Studies on the adsorption equilibrium, thermodynamics and kinetics of α-TS onto a weakly basic anion exchange resin were also carried out. This research is not only important for the production of TPGS, but also instructive for the separation of other PEG-esters from the reaction mixtures.

Cyclooxygenase-2/prostaglandin E2 inducing Effects of α-tocopheryl polyethylene glycol succinate in lung epithelial cells

Tocopherol analogs are known to have pleiotropic effects due to its interaction with diverse intracellular targets. Previously we reported that low/subapoptotic dose of α-tocopheryl succinate (αTOS) inhibits cyclooxygenase (COX) and prostaglandin E₂ (PGE₂) production in lung epithelial cells, while high dose of αTOS induces the reactive oxygen species (ROS) generation and apoptosis. In our separate study, we demonstrated that α-tocopheryl polyethylene glycol succinate (αTPGS), a polyethylene glycol (PEG)-conjugated derivative of αTOS, is a more potent ROS/apoptosis inducer compared with αTOS. The present study was prompted to examine whether PEG conjugation to αTOS also enforced its COX inhibitory activity. Of interest, we found that αTPGS failed to inhibit COX activity regardless of doses, suggesting that PEG conjugation to αTOS resulted in the loss of its COX inhibitory activity. Unexpectedly, αTPGS rather induced the COX-2 protein expression at higher/apoptotic doses. αTPGS-induced COX-2 expression was inhibited by antioxidant pretreatment. These data indicate that the COX-2 induction by αTPGS is mediated through increased ROS generation. Since the use of αTPGS as a surfactant component of dispersive drug delivery systems is frequently considered, caution should be taken when the drugs involved in COX signaling are loaded in αTPGS-included delivery systems.

Induction of DNA Damage and Caspase-Independent Programmed Cell Death by Vitamin E

Vitamin E comprises 8 functionally unique isoforms and may be a suitable candidate for the adjuvant treatment of prostate cancer. In this study, we examined the ability of 2 vitamin E isoforms [α-tocotrienol (γ-TT) and δ-tocotrienol (δ-TT)] and 4 synthetic derivatives [γ- and δ-tocotrienol succinate (γ-TS, δ-TS), α-tocopheryl polyethylene glycol succinate (TPGS), and α-tocopheryl polyethylene glycol ether (TPGS-e)] of vitamin E to induce cell death in AR− (DU145 and PC-3) and AR+ (LNCaP) prostate cancer cell lines. Our results show that δ-TT and TPGS-e are the most effective isoform and synthetic derivative, respectively, of all compounds examined. Overall, the results of our study suggest that isoforms and synthetic derivatives of vitamin E have the potency to trigger both caspase-dependent and -independent DNA damage and dominant caspase-independent programmed cell death. The capacity of vitamin E to trigger caspase-independent programmed cell death suggests that it may be useful in the chemotherapy of prostate cancer since it may prevent the tumor resistance commonly associated with the use of classical chemotherapeutic agents that trigger caspase-dependent programmed cell death.

Investigation of the micellar properties of the tocopheryl polyethylene glycol succinate surfactants TPGS 400 and TPGS 1000 by steady state fluorometry

This study has investigated the micellar properties of the d- α-tocopheryl polyethylene glycol succinate esters 400 (TPGS 400) and 1000 (TPGS 1000) in terms of critical micellar concentration (CMC), apparent aggregation number ( N agg ), microviscosity and micropolarity using steady state fluorescence techniques and fluorescent probes. In addition it has compared these properties against those of a Triton-type surfactant such as Triton X-100. The CMC values for TPGS 400, TPGS 1000 and Triton X-100 were 1.51 mM, 0.02 mM and 0.19 mM, respectively. The N agg values for TPGS 1000 and Triton X-100 were, respectively, 10 and 63. Due to the cloudiness of its aqueous solutions, no attempt was made to evaluate the microviscosity and to obtain the N agg for TPGS 400. Microviscosity at the probe site for all three surfactants was high and rather similar in spite of differences among their CMC values. The ability of TPGS 400 and TPGS 1000 to provide an environment for the fluorescence quenching of micelle-solubilized pyrene appears to be associated with their hydrophobic aromatic domains. To our knowledge the present study is the first attempt at systematically studying the micellar properties of the two most widely used TPGS compounds and of comparing these properties against each other and against those of an established nonionic surfactant.