Development of α-tocopherol surface-modified targeted delivery of 5-fluorouracil-loaded poly-D, L-lactic-co-glycolic acid nanoparticles against oral squamous cell carcinoma

Srivastava S, Gupta S, Mohammad S, Ahmad I

J Cancer Res Ther. 2019 Jul-Sep;15(3):480-490. doi: 10.4103/jcrt.JCRT_263_18.

Abstract

OBJECTIVE:

The aim of the study to develop surface modified targeted moiety α-tocopherol (α-t) encapsulated with 5-fluorouracil (5-FU)-poly-D, L-lactic-co-glycolic acid nanoparticles (PLGA NPs) toward the anticancer activity against oral squamous cell carcinoma (OSCC).

MATERIALS AND METHODS:

5-FU was conjugated with the polymer, PLGA by ionic cross-linking and α-tocopherol use as a functionalized surface moiety. Characterization, drug entrapment efficiency, and in-vitro drug release system were optimized at different pH 7.4 and pH 4.5. The in-vitro cell was performed to optimize the anticancer activity through MTT assay and apoptotic staining assay was also performed by flow cytometry to evaluate the cellular apoptotic activity and cellular uptake.

RESULTS:

The particle size was distributed within an average range of 145-162 nm, the polydispersity index values lie 0.16-0.30, and the surface charge was at the negative side, -17mV to -23mV. The in vitro drug release system showed more sympathetic situation at pH 7.4 as compared to pH 4.5, for targeted NPs, approximately 86% and 69%, respectively. The non-targeted 5-FU-PLGA NPs showed drug release of 83% and 64% at pH 7.4 and 4.5 subsequently. In vitro anticancer activity confirmed the intense inhibition by α-t-FU-PLGA NPs of 79.98% after 96 h treatment of SCC15 cells and confirmed the steady-state inhibition of 83.74% after 160 h incubation in comparison to 5-FU-PLGA NPs. Subsequently, the early apoptosis, 27.98%, and 16.45%, and late apoptosis, 47.29%, and 32.57%, suggested the higher apoptosis rate in targeted NPs against OSCC.

CONCLUSIONS:

The surface modified α-t-FU-PLGA NP was treated over SCC15 cells, and the oral cancer cells have shown the high intensity of cellular uptake, which confirmed that the target moiety has successfully invaded over the surface of cancer cells and shown advanced targeted delivery against OSCC.

Fontana F, Raimondi M, Marzagalli M, Moretti RM, Marelli MM, Limonta P

Recent Pat Anticancer Drug Discov. 2019;14(1):5-18. doi: 10.2174/1574892814666190116111827.

Abstract

BACKGROUND:

Tocotrienols (TTs) are vitamin E derivatives naturally occurring in several plants and vegetable oils. Like Tocopherols (TPs), they comprise four isoforms, α, β, γ and δ, but unlike TPs, they present an unsaturated isoprenoid chain. Recent studies indicate that TTs provide important health benefits, including neuroprotective, anti-inflammatory, anti-oxidant, cholesterol lowering and immunomodulatory effects. Moreover, they have been found to possess unique anti-cancer properties.

OBJECTIVE:

The purpose of this review is to present an overview of the state of the art of TTs role in cancer prevention and treatment, as well as to describe recent patents proposing new methods for TTs isolation, chemical modification and use in cancer prevention and/or therapy.

METHODS:

Recent literature and patents focusing on TTs anti-cancer applications have been identified and reviewed, with special regard to their scientific impact and novelty.

RESULTS:

TTs have demonstrated significant anti-cancer activity in multiple tumor types, both in vitro and in vivo. Furthermore, they have shown synergistic effects when given in combination with standard anti-cancer agents or other anti-tumor natural compounds. Finally, new purification processes and transgenic sources have been designed in order to improve TTs production, and novel TTs formulations and synthetic derivatives have been developed to enhance their solubility and bioavailability.

CONCLUSION:

The promising anti-cancer effects shown by TTs in several preclinical studies may open new opportunities for therapeutic interventions in different tumors. Thus, clinical trials aimed at confirming TTs chemopreventive and tumor-suppressing activity, particularly in combination with standard therapies, are urgently needed.

Sato A, Arai T, Fusegi M, Ando A, Yano T

Biol Pharm Bull. 2019;42(6):1034-1037. doi: 10.1248/bpb.b18-00924.

Abstract

Malignant mesothelioma (MM) is an aggressive cancer with poor prognosis. We focused on the anticancer activity of tocotrienol (T3) and have reported that a new redox-inactive T3 derivative (6-O-carboxypropyl-α-tocotrienol; T3E) exerts stronger inhibitory effects on MM cell growth than that of T3 in vitro. Furthermore, we have revealed some mechanisms of T3E that are involved in anti-MM effects. However, the effect of T3E in vivo remains unclear. In this study, we compared the plasma concentrations of T3E to that of T3 using mice to clarify differences in pharmacokinetics. Blood was sequentially collected after oral administration of T3 or T3E, and plasma concentrations were analyzed by HPLC. The area under the plasma T3 and T3E concentration-time curve from 0 to 24 h (AUC_0-24 h) of T3E was two times higher than that of T3. In addition, we evaluated the effect of T3E oral administration on tumor growth using a xenograft model of mice that were transplanted with human MM cells (H2052 cell line). Tumor volume was significantly reduced without body weight loss in mice orally administered 150 mg/kg T3E once per 2 d for 10 d, which suggests that T3E has potential anti-MM effects.

Choi Y, Lee S, Kim S, Lee J, Ha J, Oh H, Lee Y, Kim Y, Yoon Y

Int J Food Sci Nutr. 2019 Jul 12:1-5. doi: 10.1080/09637486.2019.1639637. [Epub ahead of print]

Abstract

This study evaluated if vitamin E consumption affects gut microbiota. Mice were grouped into control, low vitamin E (LV), and high vitamin E (HV). LV and HV were fed DL-α-tocopherol at 0.06 mg/20 g and 0.18 mg/20 g of body weight per day, respectively, for 34 days. Body weight of mice was measured before and after vitamin E treatment. Animals were sacrificed, liver, spleen, small intestine and large intestine collected, and weight and length were measured. Composition of gut microbiota was determined by microbiome analysis. Spleen weight index of LV was the highest. However, liver weight indices and intestinal lengths were not different. Body weights of LV group were higher than those of control. Ratio of Firmicutes to Bacteroidetes was different in LV compared to control and HV. These results indicate that low-level consumption of vitamin E increases spleen and body weight, and changes gut microbiota.

Choe MS, Yeo HC, Bae CM, Han HJ, Baek KM, Kim JS, Lim KS, Shin IS, Chang WC, Yun SP, Lee HJ, Lee MY

Cell Biol Int. 2019 Jul 10. doi: 10.1002/cbin.11200. [Epub ahead of print]

Abstract

Cardiac differentiation of human pluripotent stem cells may be induced under chemically defined conditions, wherein the regulation of Wnt/β-catenin pathway is often desirable. Here, we examined the effect of trolox, a vitamin E analog, on the cardiac differentiation of human embryonic stem cells (hESCs). Trolox significantly enhanced cardiac differentiation in a time- and dose-dependent manner after the mesodermal differentiation of hESCs. Trolox promoted hESC cardiac differentiation through its inhibitory activity against the Wnt/β-catenin pathway. This study demonstrates an efficient cardiac differentiation method and reveals a novel Wnt/β-catenin regulator.

Casati L, Pagani F, Limonta P, Vanetti C, Stancari G, Sibilia V

Eur J Nutr. 2019 Jul 6. doi: 10.1007/s00394-019-02047-9. [Epub ahead of print]

Abstract

PURPOSE:

Natural antioxidants are considered as promising compounds in the prevention/treatment of osteoporosis. We studied the ability of purified δ-tocotrienol (δ-TT) isolated from a commercial palm oil (Elaeis guineensis) fraction to protect osteoblast MC3T3-E1 and osteocyte MLO-Y4 cells against tert-butyl hydroperoxide (t-BHP)-induced oxidative damage and the mechanisms involved in its protective action in MC3T3-E1.

METHODS:

MC3T3-E1 and MLO-Y4 cells were treated with δ-TT (1.25-20 µg/ml for 2 h) followed by t-BHP at 250 µM or 125 µM for 3 h, respectively. MTT test was used to measure cell viability. Apoptotic cells were stained with Hoechst-33258 dye. Intracellular ROS levels were measured by dichlorofluorescein CM-DCFA. The OPT fluorimetric assay was used to detect the reduced glutathione to oxidized glutathione ratio (GSH/GSSG) contents.

RESULTS:

δ-TT significantly prevented the effects of t-BHP on cell viability and apoptosis reaching a maximum protective activity at 10 and 5 µg/ml in MC3T3-E1 and MLO-Y4 cells, respectively. This protective effect was due to a reduction of intracellular ROS levels and an increase in the defense systems shown by the increase in the GSH/GSSG. GSH loss induced by an inhibitor of GSH synthesis significantly reduced the δ-TT-positive effect on ROS levels. δ-TT prevention of oxidative damage was completely removed by combined treatment with the specific inhibitors of PI3K/AKT (LY294002) and Nrf2 (ML385).

CONCLUSIONS:

The δ-TT protective effect against oxidative damage in MC3T3-E1 cells is due to a reduction of intracellular ROS levels and an increase of the GSH/GSSG ratio, and involves an interaction between the PI3K/Akt-Nrf2 signaling pathways.

Nasef SM, Khozemy EE, Kamoun EA, El-Gendi H

Int J Biol Macromol. 2019 Jul 5;137:878-885. doi: 10.1016/j.ijbiomac.2019.07.033. [Epub ahead of print]

Abstract

Crosslinked hydrogel composite membranes based on polyvinyl alcohol (PVA) and chitosan-loaded AgNO₃ and vitamin E were prepared using gamma irradiation. Chitosan has been used as antimicrobial blend materials to provide further biocompatibility for the prepared composite hydrogel membranes. The crosslinking reaction between PVA and chitosan owing to gamma irradiation was verified and characterized by FTIR analysis, while the morphology of hydrogel composite membranes was investigated by SEM. Important parameters affecting on hydrogel membranes formation, such as copolymer concentration, irradiation dose, AgNO₃ concentration, plasticizer, and vitamin E of PVA/chitosan membranes were evaluated and discussed in details. In addition, the mechanical and thermal properties of hydrogel composite membranes were examined to evaluate the possibility of its application for wound dressings. The results revealed that the gelation (%) of hydrogel membranes increased dramatically with PVA composition, irradiation dose and glycerol content up to 20%; however, it decreased with AgNP incorporation due to the viscosity of copolymer composition is hyper-increased. The swelling ratio of composed hydrogel membranes decreased notably with increasing the radiation dose and incorporation of AgNP, due to reducing of the crosslinking degree of formed hydrogel membranes. PVA-Cs-Ag composed hydrogel membranes showed significant antimicrobial activity in particular against Streptococcus mutans due to the presence of AgNP in membranes, compared to other bacteria and fungi microbes. Thus, the PVA/chitosan/AgNO₃-Vit.E hydrogel composite membranes showed satisfactory properties for use as wound dressing materials.

Ivancovsky-Wajcman D, Fliss-Isakov N, Salomone F, Webb M, Shibolet O, Kariv R, Zelber-Sagi S

Dig Liver Dis. 2019 Jul 4. pii: S1590-8658(19)30662-0. doi: 10.1016/j.dld.2019.06.005. [Epub ahead of print]

Abstract

BACKGROUND & AIMS:

Although antioxidants have a protective potential in nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), there is limited evidence regarding the role of dietary intake of antioxidants. The aim was to test the association between dietary vitamins E and C intake and NAFLD, NASH and fibrosis markers.

METHODS:

Cross-sectional study of a large cohort of subjects undergoing colonoscopy. The presence of NAFLD was evaluated by ultrasonography. The level of steatosis was defined using SteatoTest, moderate-severe NASH using new quantitative NashTest and borderline-significant fibrosis ≥ F1-F2 using FibroTest. Nutritional intake was measured by food frequency questionnaire (FFQ).

RESULTS:

Overall, 789 subjects were included (52.6% men, age 58.83 ± 6.58 years), 714 had reliable FibroMax. Adjusting for BMI, dietary and lifestyle factors, the upper tertile of vitamin E intake/1000 Kcal was associated with lower odds of NASH (OR = 0.64, 0.43-0.94, P = 0.024). There was an inverse association between reaching the recommended vitamin E intake and NASH (OR = 0.48, 0.30-0.77, P = 0.002). The upper tertile of vitamin C intake/1000 Kcal was associated with lower odds of NAFLD and NASH (OR = 0.68, 0.47-0.99, P = 0.045; OR = 0.57, 0.38-0.84, P = 0.004, respectively). Both vitamins were related with the level of steatosis according to SteatoTest.

CONCLUSION:

Vitamin E and C intake may be protective from NAFLD-related liver damage.