PEGylated phospholipid micelles containing D-α-tocopheryl succinate as multifunctional nanocarriers for enhancing the antitumor efficacy of doxorubicin

Weiwei Jiang, Qing Fan, Jing Wang, Bingning Zhang, Tangna Hao, Qixian Chen, Lei Li, Lixue Chen, Hongxia Cui, Zhen Li

Int J Pharm . 2021 Aug 6;120979. doi: 10.1016/j.ijpharm.2021.120979. Online ahead of print.

Abstract

The aim of this investigation is to clarify the effect of D-α-tocopheryl succinate (vitamin E succinate, VES) and distearoylphosphatidyl ethanolamine-poly(ethylene glycol) (DSPE-PEG) on the encapsulation and controlled release of doxorubicin (DOX) in nano-assemblies and their consequences on the anti-tumor efficacy of DOX. DOX molecules were successfully loaded into the hybrid micelles with VES and DSPE-PEG (VDPM) via thin-film hydration method, exhibiting a small hydrodynamic particle size (∼30 nm) and a weak negative zeta potential of around -5 mv. The obtained DOX-loaded VDPM2 displayed retarded DOX release at pH of 7.4, while substantially accelerated drug release at acidic pH of 5.0. Furthermore, the DOX-loaded VDPM2 exhibited substantially slower drug release rate at pH 7.4 compared with the drug-loaded VDPM1 or DPM preparation, benefiting for decreasing the premature DOX release during blood circulation. In vitro cell experiment indicated that DOX-Loaded micelles (DPM, VDPM1 and VDPM2) improved the cellular uptake of DOX in 4T1 and MDA-MB-231 cells. The existence of VES component in the structure of DOX-loaded micelles had no obvious influence on the subcellular distribution of the encapsulated DOX molecules. However, the DOX-loaded VDPM2 exhibited more pronounced cytotoxicity to 4T1 and MDA-MB-231 cancerous cells compared with DOX-loaded DPM and free DOX solution. The hybrid nanocarriers including VES and DSPE-PEG selectively induced intracellular ROS accumulation and increased level of cytoplasmic calcium ion in cancerous cells by interacting with mitochondria and endoplasmic reticulum, bringing about the improved cytotoxicity of DOX. In vivo antitumor efficacy investigation of DOX-loaded VDPM2 against 4T1 xenograft-bearing mice displayed satisfied therapeutic activity with negligible systemic toxicity, as evidenced by the histological analysis and change of body weight. The proposed DOX-loaded VDPM preparation, as a mulifunctional chemotherapeutic nanomedicine system, holds great potential and bright prospect for clinical tumor therapy.

Silvia Romero-Maldonado, Araceli Montoya-Estrada, Enrique Reyes-Muñoz, Alberto Martín Guzmán-Grenfell, Yessica Dorin Torres-Ramos, Mario David Sánchez-Mendez, Maricruz Tolentino-Dolores, Manuel Bernardo Salgado-Valladares, Aurora Belmont-Gómez, Nayelli Najéra, Guillermo Ceballos, Jorge Arturo Cardona-Pérez, Juan José Hicks, Javier Mancilla-Ramírez

Medicine (Baltimore) . 2021 Aug 6;100(31):e26765. doi: 10.1097/MD.0000000000026765.

Abstract

Background:: Vitamin E has antioxidant properties, which help in scavenging free radicals, thereby reducing oxidation of lipids and proteins. This study aims to evaluate the efficacy of oral vitamin E supplementation in preventing retinopathy of prematurity (ROP) in very low birth weight (VLBW) infants with respiratory distress syndrome (RDS) and decreasing oxidative stress 15 and 28 days post-intervention.

Methods:: Ninety VLBW infants were randomly assigned to two groups:

1.Treatment (treatment group (T), n = 48) or
2.Placebo (control group (C), n = 42).

Each group received 25 IU of vitamin E (T) or placebo (C).

Results:: The incidence of ROP in groups T and C was 12.5% (n=6) and 31% (n = 13), respectively (RR: 0.40; 95% CI: 0.10–0.96). There were no differences in mortality between groups. As expected, the vitamin E concentration was significantly increased 28 days post-intervention in group T.

Conclusion:: Oral supplementation with vitamin E may effectively prevent ROP development in VLBW infants with RDS. Oxidative damage markers were significantly lower, whereas total antioxidant capacity was increased in group T. However, levels of other antioxidants as vitamin A and C were not measured in two groups.

Temitayo Olabisi Ajibade, Foluso B Bolaji-Alabi, Ademola Adetokunbo Oyagbemi, Ifeoluwa W Ajileye, Temidayo Olutayo Omobowale

J Basic Clin Physiol Pharmacol . 2021 Aug 6. doi: 10.1515/jbcpp-2020-0097. Online ahead of print.

Abstract

Objectives: Ovariectomy induces heightened response to vasoconstrictors, alters vasorelaxation and consequently causes hypertension due to increased oxidative stress in rats.

Methods: This study evaluated the ameliorative effects of ramipril and vitamin E, on primary haemodynamic parameters and cardiac antioxidant defence status, in ovariectomised rats using 64 adult female rats of the Wistar strain randomly divided as follows: Control (sham); Ovariectomised (OVX); OVX plus Ramipril; OVX plus vitamin E; and OVX plus Ramipril plus vitamin E.

Results: The plasma level of oestrogen was significantly lower (p<0.05), in the ovariectomised rats compared with the sham. The systolic, diastolic and mean arterial blood pressure of ovariectomised rats increased significantly (p<0.05), but the alteration was significantly reduced by the administration of ramipril alone or in combination with vitamin E. Significant decrease (p<0.05) was observed in the serum level of nitric oxide in OVX group compared with Sham. Also, analysed markers of oxidative stress: Malondialdehyde (MDA) contents and hydrogen peroxide (H₂O₂) generated decreased significantly (p<0.05), but systemic antioxidants: reduced glutathione (GSH) contents; glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities increased significantly (p<0.05) in the ovariectomised rats treated with ramipril and vitamin E compared with untreated ovariectomised rats. The study concludes that alteration, in the primary haemodynamic parameters, associated with ovariectomy in rats is potently ameliorated by co-administration of the antihypertensive drug ramipril and vitamin E.

Conclusions: The supplementation of antihypertensive regimen with antioxidants such as vitamin E in the treatment of hypertension is therefore justifiable especially in ovariectomised or hypogonadal patients.

Kingsley Dominic Esu, Ahmed Olalekan Bakare, Bamidele Victor Owoyele

Pain Pract . 2021 Aug 5. doi: 10.1111/papr.13064. Online ahead of print.

Abstract

Objectives: This study investigated the antinociceptive effects of co-administration of lithium chloride (LiCl) and vitamin E (Vit. E) on chronic constriction injury (CCI)-induced peripheral neuropathy in male Wistar rats. It further explored the anti-inflammatory and neuroprotective properties of LiCl and Vit. E which may be complementary to the antinociceptive effects of the two substances.

Methods: Thirty-six male Wistar rats, 190.00 ± 10.00 g of body weight (b.w) were randomly assigned to six experimental groups and administered with either normal saline, Vit. E, LiCl, or their combination, once daily for twenty-one (21) days. CCI was used to induce NP and mechanical allodynia was assessed using von Frey filaments and pinprick test. Open field maze (OFM) was used to assess the exploratory behaviour. Biochemical parameters were assessed in the dorsal root ganglion (DRG) after twenty-one days of treatment.

Results: Mechanical allodynia was developed in rats following CCI. Co-administration of LiCl and Vit.E. synergistically reduced mechanical hyperalgesia in rats which were significantly different compared with the single administration of either Vit.E. or LiCl. Combined doses of Vit.E. and LiCl significantly increases the explorative behaviour in the OFM. CCI increased malondialdehyde (MDA), tumour necrotic factor-alpha (TNF-α), calcitonin gene-related polypeptide (CGRP), calcium ion (Ca²⁺ ), and reduced superoxide dismutase (SOD) activities. Co-administration of LiCl and Vit.E. significantly reduced MDA, TNF-α, but increased SOD compared with ligated control.

Discussion: The findings revealed that the synergistic effects of the co-administration of Vit. E and LiCl in ameliorating neuropathic pain are mediated by their anti-inflammatory and antioxidant properties.

Yaw Opoku-Damoah, Run Zhang, Hang T Ta, Zhi Ping Xu

Biomater Sci . 2021 Aug 4. doi: 10.1039/d1bm00941a. Online ahead of print.

Abstract

The quest to maximize therapeutic efficiency in cancer treatment requires innovative delivery nanoplatforms capable of employing different modules simultaneously. Combination therapy has proven to be one of the best anticancer strategies so far. Herein, we have developed a lipid-encapsulated nanoplatform that combines chemotherapy with photoresponsive gas therapy for colon cancer treatment. Carbon monoxide releasing molecules (CORMs) and vitamin E analogues (pure/pegylated α-tocopheryl succinate; α-TOS) were co-loaded into the lipid layer with core-shell upconversion nanoparticles (UCNPs), which converted 808 nm light to 360 nm photons to trigger CO release at the tumor site. This folic acid (FA)-targeting nanomedicine (Lipid/UCNP/CORM/α-TOS/FA: LUCTF) possessed a cancer-targeting ability and a light-triggered CO release ability for synergistic apoptosis of HCT116 cells via enhanced ROS generation and mitochondrial membrane breaking. In vivo data have confirmed the significantly enhanced therapeutic efficacy of LUCTF without any significant biosafety issues after intravenous administration. Thus, nanomedicine LUCTF represents a novel way for efficient cancer therapy via combining locally released CO and a compatible chemotherapeutic agent (e.g. α-TOS).

Erdi Sozen, Tugce Demirel-Yalciner, M Kutay Koroglu, Merve Acikel Elmas, Feriha Ercan, Nesrin Kartal Ozer

IUBMB Life . 2021 Aug 4. doi: 10.1002/iub.2535. Online ahead of print.

Abstract

The seminiferous tubules where spermatogenesis occurs are enveloped and protected by the Sertoli cells to support germ cells undergoing meiosis to produce haploid gametes. Clearly, induction of apoptosis in seminiferous tubules leads to abnormalities in spermatogenesis and male infertility. Studies demonstrated that increased hyperlipidemia impairs male infertility and spermatogenesis by enhancing seminiferous tubules apoptosis. However, molecular mechanisms underlying high-cholesterol-mediated testicular damage remain poorly elucidated. In this scope, we established a rabbit model and investigated the role of endoplasmic reticulum (ER) stress on high cholesterol diet induced seminiferous tubule apoptosis. Histopatological examinations revealed increased seminifer tubule apoptosis in testes of rabbits fed high cholesterol diet. In addition, phosphorylated forms of IRE1 and PERK, two well-identified markers of ER stress, were significantly induced in accordance with high cholesterol diet. High cholesterol diet also exhibited CHOP induction in testes, indicating increased ER stress related apoptosis. Supplementation of α-tocopherol significantly attenuated cholesterol mediated ER stress, and restored seminiferous tubules apoptosis. Taken together, our findings suggest that α-tocopherol might be capable to reduce testicular damage via ameliorating histopatological features and inhibiting seminiferous tubules apoptosis in hypercholesterolemic rabbits.

Yiu-Tai Li, Wen-Ling Lee, Peng-Hui Wang

J Chin Med Assoc . 2021 Aug 1;84(8):739-740. doi: 10.1097/JCMA.0000000000000566.

Abstract

It is well known that adequate maintenance or support of nutrition during pregnancy, including essential and trace elements and calorie intake, is a critical dimension not only to maintain peak health and performance of themselves but also for the lifelong health of the offspring.^1–7 Malnutrition often results in inadequate protein intake, fewer calories, and deficiency of certain-type essential trace elements. Intake of enough calorie can be easily monitored by measuring gestational weight gain (GWG) in the entire pregnancy period or more accurately estimated by separating GWG according to the different trimesters³; however, it is hard to define whether these pregnant women have adequate dietary intake or meet recommendations for vitamins D, C, A, B complex, K, and E, as well as folate, choline, iron, calcium, potassium, magnesium, zinc, and other essential trace elements (minerals or essential amino acids and so on), partly because of difficulty to measure and monitor these essential trace elements, and partly because of overlooking its important and critical role on both maternal and offspring’s outcome.¹^,²^,^4–6 Additionally, these certain-type essential trace elements sometimes make physicians or healthcares confused, based on the presence of multifaced functions of these elements. It has been reported that continuous supplementation of vitamin E throughout offspring lifespan provides beneficial effects to the offspring, but one meta-analysis using experimental models and observational investigations, which are involved with more than 135 000 participants in 19 trials carried out between 1966 and 2004 did not support the above-mentioned findings, based on a significantly increasing mortality from all causes when high dosage vitamin E supplements are given as a supplement throughout their lifespan.

Kristen N. Owen, Olga Dewald

In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan. 2021 Aug 1.

Excerpt

Vitamin E is a major lipid-soluble antioxidant obtained exclusively from the diet. It was discovered in the 1920s as an essential dietary element required by rats for reproduction. There are approximately eight different vitamin E-related molecules, but the dominant molecule in humans is alpha-tocopherol. Tocotrienols are the other molecules that are widely studied for vitamin E supplementation. These two molecules have been studied in various dosages and for many different health purposes. Vitamin E has peroxyl radical scavenger properties. While vitamin E toxicity is associated with an increased risk of bleeding, its deficiency has been associated with neurologic diseases and anemia.

Shonia Subramaniam, Jeya Seela Anandha Rao, Premdass Ramdas, Mei Han Ng, Methil Kannan Kutty, Kanga Rani Selvaduray, Ammu Kutty Radhakrishnan

Clin Exp Immunol . 2021 Jul 31. doi: 10.1111/cei.13650. Online ahead of print.

Abstract

Gamma-tocotrienol (γT3) is an analogue of vitamin E with beneficial effects on the immune system, including immune-modulatory properties. This study reports the immune-modulatory effects of daily supplementation of γT3 on host T-helper (Th) and T-regulatory (Treg) populations in a syngeneic mouse model of breast cancer. Female BALB/c mice were fed with either γT3 or vehicle (soy oil) for 2-weeks via oral gavage before they were inoculated with syngeneic 4T1 mouse mammary cancer cells (4T1 cells). Supplementation continued until the mice were sacrificed. Mice (n=6) were sacrificed at specified time-points for various analysis (blood leucocyte, cytokine production, and immunohistochemistry). Tumour volume was measured once every seven days. Gene expression studies were carried out on tumour-specific T-lymphocytes isolated from splenic cultures. Supplementation with γT3 increased CD4⁺ (p<0.05), CD8⁺ (p<0.05) T-cells and natural killer cells (p<0.05) but suppressed Treg cells (p<0.05) in peripheral blood when compared to animals fed with the vehicle. Higher interferon-gamma (IFNγ) and lower transforming growth factor-beta (TGF-ꞵ) levels were noted in the γT3 fed mice. Immunohistochemistry findings revealed higher infiltration of CD4⁺ cells, increased expression of interleukin-12 receptor-beta-2 (IL-12ꞵ2R), interleukin-24 (IL-24) and reduced expression of cells that express the forkhead box P3 (FoxP3) in tumours from the γT3 fed animals. Gene expression studies showed the downregulation of seven prominent genes in splenic CD4⁺ T-cells isolated from γT3-fed mice. Supplementation with γT3 from palm oil-induced T-cell dependent cell-mediated immune responses and suppressed Treg cells in the tumour microenvironment in a syngeneic mouse model of BC.

Erin N Hales, Hadi Habib, Gianna Favro, Scott Katzman, R Russell Sakai, Sabin Marquardt, Matthew H Bordbari, Brittni Ming-Whitfield, Janel Peterson, Anna R Dahlgren, Victor Rivas, Carolina Alanis Ramirez, Sichong Peng, Callum G Donnelly, Bobbi-Sue Dizmang, Angelica Kallenberg, Robert Grahn, Andrew D Miller, Kevin Woolard, Benjamin Moeller, Birgit Puschner, Carrie J Finno

J Vet Intern Med . 2021 Jul 31. doi: 10.1111/jvim.16233. Online ahead of print.

Abstract

Background: Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is an inherited neurodegenerative disorder associated with a vitamin E deficiency within the first year of life. Vitamin E consists of 8 isoforms metabolized by the CYP4F2 enzyme. No antemortem diagnostic test currently exists for eNAD/EDM.

Hypothesis/objectives: Based on the association of α-tocopherol deficiency with the development of eNAD/EDM, we hypothesized that the rate of α-tocopherol, but not γ-tocopherol or tocotrienol metabolism, would be increased in eNAD/EDM-affected horses.

Animals: Vitamin E metabolism: Proof of concept (POC) study; eNAD/EDM-affected (n = 5) and control (n = 6) horses. Validation study: eNAD/EDM-affected Quarter Horses (QHs; n = 6), cervical vertebral compressive myelopathy affected (n = 6) horses and control (n = 29) horses. CYP4F2 expression and copy number: eNAD/EDM-affected (n = 12) and age- and sex-matched control (n = 11-12) horses.

Methods: The rates of α-tocopherol/tocotrienol and γ-tocopherol/tocotrienol metabolism were assessed in equine serum (POC and validation) and urine (POC only) using liquid chromatography tandem mass spectrometry (LC-MS/MS). Quantitative reverse-transcriptase PCR (qRT-PCR) and droplet digital (dd)-PCR were used to assay expression and genomic copy number of a CYP4F2 equine ortholog.

Results: Metabolic rate of α-tocopherol was increased in eNAD/EDM horses (POC,P < .0001; validation, P = .03), with no difference in the metabolic rate of γ-tocopherol. Horses with eNAD/EDM had increased expression of the CYP4F2 equine orthologue (P = .02) but no differences in copy number.

Conclusions and clinical importance: Increased α-tocopherol metabolism in eNAD/EDM-affected QHs provides novel insight into alterations in vitamin E processing in eNAD/EDM and highlights the need for high-dose supplementation to prevent the clinical phenotype in genetically susceptible horses.