Tocopherol Derivatives Research Articles

Study of functional lipid nanoparticles for mRNA delivery using new ionizable tocopherol derivatives

AbstractIn this study, tocopherol‐derived ionizable lipids were synthesized to create functional lipid nanoparticles for mRNA delivery. Tocopherol succinate is considered a biocompatible material because it has anti‐cancer effects and degrades into vitamin E in the body. Two types of new ionizable tocopherol derivative lipids (DMT and AIT) were synthesized by introducing ionizable functional groups. The synthesized tocopherol lipids were used to make lipid nanoparticles with helper lipid, cholesterol, and PEG‐DMG. The DMT LNP showed high mRNA encapsulation efficiency. Using HeLa cell lines, it was confirmed that gene transfection efficiency was increased approximately 2‐fold in DMT LNP‐treated cells compared to that of MC3 LNP. The two types of tocopherol derivative lipids exhibited high cell viability of over 90%, confirming very low levels of toxicity. The results of this study confirmed that lipid nanoparticles using newly developed ionizable tocopherol derivatives have potential as biocompatible and effective mRNA delivery vehicles.

Anticancer Potential of Tocopherols-Containing Plants and Semi-Synthetic Tocopherols.

Tocopherols, potent bioactive compounds with anticancer properties, remain understudied in herbal medicinal plants, presenting a significant knowledge gap in the field of natural anticancer agents. This review evaluates tocopherol-containing plants for their anticancer potential, analyzing Scopus publications from 2016 to 2024. Fifteen herbal medicinal plants were identified as promising candidates, including Bulbine anguistifolia Poelln, Punica granatum L., Moringa oleifera, Kigelia pinnata, and Typhonium flagelliforme Lodd. The review explores tocopherols' anticancer mechanisms, including apoptosis induction and cell cycle arrest. Factors influencing tocopherols' anticancer effects are examined, such as their forms (α, β, γ, δ), concentrations, plant parts utilized, and their stability in various plants. Additionally, emerging research on semi-synthetic tocopherol derivatives is analyzed, highlighting their potential as adjuvants in chemotherapy and their role in enhancing drug delivery and reducing side effects. This comprehensive analysis aims to advance the development of plant-based anticancer pharmaceuticals and improve cancer treatment strategies. By elucidating the mechanisms and potential of tocopherol-containing plants, this review provides a foundation for future research in plant-based anticancer therapies. It emphasizes the need for further investigation into these plants' anticancer properties, potentially leading to novel, more effective, and less toxic cancer therapies. The findings presented here contribute to a nuanced understanding of how tocopherol-containing plants can be leveraged in the development of future anticancer drugs.

New tocopherol and acylphloroglucinol derivatives from Dryopteris crassirhizoma and their antimicrobial activities

Nine previously undescribed compounds including six tocopherol derivatives (1–6) and three acylphloroglucinol derivatives (7–9) were isolated and characterized from the plants of Dryopteris crassirhizoma. Their structures with absolute configurations were determined by extensive spectroscopic analyses, including IR, HRESIMS, NMR, and calculated electronic circular dichroism (ECD). Compounds 1 and 2 are the first tocopheroid derivatives possessing unique 2,5-dimethylcyclopent-4-ene-1,3-dione carbon skeleton, and compounds 3–6 were new 5a-norcyclopentenones having a spirofused bicyclic carbon skeleton. The biosynthetic pathway of compounds 1–6 was postulated. When combined with fluconazole (FLC), compound 3 showed significant antifungal activity against standard Candida albicans with MIC50 value of 1.19 μg/mL (FLC: 3.41 μg/mL). Furthermore, the anti-plant pathogenic fungi and bacterial activities have been evaluated in vitro, compounds 5 and 8 showed anti-Verticillium dahlia and Sclerotinia sclerotiorum with MIC value of 50 μg/mL, respectively. Compounds 1 and 5 exhibited moderate antibacterial activities against Micrococcus luteus with MIC value of 50 μg/mL, respectively.

Inhibition of Oxidative Stress and the NF-κB Pathway by a Vitamin E Derivative: Pharmacological Approach against Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. In this study, PD was induced via (ip) injection of haloperidol (1 mg/kg/day). Animals were divided into seven groups (n = 70). Group I received the vehicle carboxymethylcellulose (CMC; 0.5%), group II was treated with designated 1 mg/kg haloperidol, and group III received the standard drug Sinemet (100 mg/kg), while groups IV-VII received a tocopherol derivative (Toco-D) at dose levels of 5, 10, 20, and 40 mg/kg, respectively, via the oral route. All groups received haloperidol for 23 consecutive days after their treatments except the control group. The improvement in locomotor activity and motor coordination was evaluated by using behavioral tests. Oxidative stress markers, neurotransmitters, and monoamine oxidase B (MAO-B) as well as NF-κB levels in the whole brain were measured. mRNA expression analysis of α-synuclein was carried out using the PCR technique. Toco-D at 20 mg/kg showed the maximum improvement in locomotor activity. The levels of antioxidant enzymes and neurotransmitters were also increased by the treatment with Toco-D. Inflammatory cytokine levels and mRNA expression of α-synuclein were decreased by Toco-D in treated animals. This study concluded that Toco-D might be effective in the improvement of locomotor activity and motor coordination in haloperidol-induced PD.

Phytochemical Profiling, Antioxidant, Antimicrobial and Cholinesterase Inhibitory Effects of Essential Oils Isolated from the Leaves of Artemisia scoparia and Artemisia absinthium.

The current studies were focused on the phytochemical profiling of two local wild Artemisia species, Artemisia scoparia and Artemisia absinthium leaves’ essential oils, extracted via the hydro distillation method along with evaluation of their antioxidant as well as antimicrobial effects. The constituents of EOs were identified using a combined gas chromatography-mass spectrometric (GC-MS) technique. A total of 25 compounds in A. scoparia essential oil (EOAS) were identified, and 14 compounds with percentage abundance of >1% were tabulated, the major being tocopherol derivatives (47.55%). A total of nine compounds in Artemisia absinthium essential oil (EOAA) were enlisted (% age > 1%), the majority being oleic acid derivatives (41.45%). Strong antioxidant effects were pronounced by the EOAS in DPPH (IC50 = 285 ± 0.82 µg/mL) and in ABTS (IC50 = 295 ± 0.32 µg/mL) free radical scavenging assays. Both the EOs remained potent in inhibiting the growth of bacterial species; Escherichia coli (55–70%) and Shigella flexneri (60–75%) however remained moderately effective against Bacillus subtilis as well as Staphylococcus aureus. Both EOAS and EOAA strongly inhibited the growth of the tested fungal species, especially Aspergillus species (up to 70%). The oils showed anti-cholinesterase potential by inhibiting both Acetylcholinesterase (AChE; IC50 = 30 ± 0.04 µg/mL (EOAS), 32 ± 0.05 µg/mL (EOAA) and Butyrylcholinesterase (BChE; IC50 = 34 ± 0.07 µg/mL (EOAS), 36 ± 0.03 µg/mL (EOAA). In conclusion, the essential oils of A. scoparia and A. absinthium are promising antioxidant, antimicrobial and anticholinergic agents with a different phytochemical composition herein reported for the first time.

New Tocopherol and Acylphloroglucinol Derivatives from Dryopteris Crassirhizoma and Their Antimicrobial Activities

New Tocopherol and Acylphloroglucinol Derivatives from Dryopteris Crassirhizoma and Their Antimicrobial Activities

(Trifluoromethylselenyl)methylchalcogenyl as Emerging Fluorinated Groups: Synthesis under Photoredox Catalysis and Determination of the Lipophilicity.

The synthesis of molecules bearing (trifluoromethylselenyl)methylchalcogenyl groups is described via an efficient two-step strategy based on a metal-free photoredox catalyzed decarboxylative trifluoromethylselenolation with good yields up to 88 %, which raised to 98 % in flow chemistry conditions. The flow methods allowed also to scale up the reaction. The mechanism of this key reaction was studied. The physicochemical characterization of these emerging groups was performed by determining their Hansch-Leo lipophilicity parameters with high values up to 2.24. This reaction was also extended to perfluoroalkylselenolation with yields up to 95 %. Finally, this method was successfully applied to the functionalization of relevant bioactive molecules such as tocopherol or estrone derivatives.

A physiological examination of the antioxidant ability of super tocopherol derivatives

A quantum-chemical study on some super tocopherol derivatives and their heavier chalcogen derivatives has been undertaken to evaluate the antioxidant abilities through different mechanistic pathways. The effect of different solvent media, including the lipid environment, on their antioxidant ability has also been explored. This study reveals that the incorporation of heavier chalcogen not only increases the antioxidant abilities of the super tocopherol derivatives but also makes them physiologically more active. The heavier analogs can scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical through H-atom transfer. The stability of the antioxidant free radicals is due to the presence of non-covalent chalcogen–chalcogen interactions, which increase with the incorporation of heavier chalcogen atoms into the super tocopherol derivatives.

New tocopherol derivatives for functionalization of amino or carboxyl groups with lipid anchors

New tocopherol derivatives for functionalization of amino or carboxyl groups with lipid anchors

α-Tocopheryl succinate stabilizes the structure of tumor vessels by inhibiting angiopoietin-2 expression

α-Tocopheryl succinate (TS) is a tocopherol derivative and has multifaceted anti-cancer effects; TS not only causes cancer cell-specific apoptosis but also inhibits tumor angiogenesis. Although TS has the potential to be used as a well-tolerated anti-angiogenic drug, it is still unclear which step of the angiogenic process is inhibited by TS. Here, we show that TS inhibits the expression of angiopoietin (Ang)-2, which induces destabilization of vascular structure in the initial steps of the angiogenic process. In mouse melanoma cells, TS treatment decreased mRNA and extracellular protein levels of Ang-2; however, the mRNA level of Ang-1, which stabilizes the vascular structure, remained unchanged. Furthermore, aorta ring and Matrigel plug angiogenesis assays indicated that the conditioned medium from TS-treated cells (CM-TS) inhibited neovascularization and blood leakage from the existing blood vessels, respectively. Following immunohistochemical staining of the vessels treated with CM-TS, imaging studies showed that the vascular endothelial cells were highly packed with pericytes. In conclusion, we found that TS inhibits Ang-2 expression and, consequently, stabilizes the vascular structure during the initial step of tumor angiogenesis.

Differential Effects of TPM, A Phosphorylated Tocopherol Mixture, and Other Tocopherol Derivatives as Excipients for Enhancing the Solubilization of Co-Enzyme Q10 as a Lipophilic Drug During Digestion of Lipid- Based Formulations.

The tocopherol-based excipient, TPM, when incorporated into a medium-chain triglyceride (MCT)-based lipid formulation, has been previously shown to improve the solubilization of Coenzyme Q10 (CoQ10) during in vitro digestion which is strongly correlated with enhanced exposure in vivo. The current study aimed to gain further understanding of the MCT + TPM co-formulation, by assessing the formulation performance under fasted and fed in vitro digestion conditions, with different drug and excipient loading levels. Natural and synthetic-derived TPM were equivalent, and with d-α- tocopherol polyethylene glycol 1000 succinate (TPGS) outperformed other derivatives in enhancing the solubilisation of CoQ10 during digestion. Fed conditions significantly improved the solubility of CoQ10 during in vitro digestion of the formulation in comparison with fasted conditions. The addition of TPM at 10% (w/w) of the total MCT + TPM provided optimal performance in terms of CoQ10 solubilization during digestion. The results further highlights the potential of TPM as an additive in lipid formulations to improve the solubilization and oral bioavailability of poorly water-soluble compounds.

Evolution of the use of antioxidants in anti‐ageing cosmetics

Skin health and beauty are a cornerstone of general well-being in humans. Anti-ageing cosmetics are used to provide a healthy and youthful appearance. Among the different cosmetic actives, antioxidants are incorporated in anti-ageing products due to their beneficial effects in preventing and minimizing the signs of skin ageing. This work aims to understand how anti-ageing formulations changed in the past 7years regarding pure antioxidants composition. Data were collected from anti-ageing formulations commercialized in main stores and pharmacies in the Portuguese market. The study started on 2011 and was updated with products launched or whose composition has been renewed on 2013, 2015 or 2018. Ascorbic acid and tocopherol and their derivatives were consistently the most used antioxidants in anti-ageing formulations; followed by niacinamide and retinyl palmitate. Seven ascorbic acid derivatives are currently used in anti-ageing formulations while only three tocopherol derivatives were identified in this study. Several combinations of antioxidants were routinely found, mainly tocopherol (or tocopherol derivatives) with other antioxidants and tocopherol with tocopherol derivatives. We have not identified emerging antioxidants with great impact in anti-ageing formulations even though niacinamide and retinyl palmitate exhibited over 10% more usage in 2018. This insight is relevant to the cosmetic industry providing a better understanding of the scientific-based formulation of modern cosmetics and supports the need for innovative antioxidants in anti-ageing cosmetics.

Development of a Flow-Injection ESR System for Evaluating the Lipophilic Alkoxyl Radical Eliminating Capacities (L-AREC) of Tocopherol Analogues and Unsaturated Fatty Acids

Abstract A new lipophilic spin-trapping flow-injection electron spin resonance (LFI-ESR) system was developed for quantitative detection of DMPO spin-adduct of alkoxyl radical (RO•), which was produced by thermal decomposition of an azo-initiator (AIBN) in ethyl acetate at 70 °C. The 50% and 75% inhibition dose (ID50 and ID75) of a series of lipophilic antioxidants, such as tocopherol derivatives (αToc, βToc, γToc, δToc, Toc, αTocM, βTocM, γTocM, TocM, TRX, and 7TocM), a lipophilic phenol (BHT), and unsaturated fatty acids (Ole, Lin, and Lic), were determined by monitoring the ESR signal intensity of the DMPO spin-adducts of RO• radical (DMPO/OR). On the basis of the observed ID50 and ID75 values, the lipophilic alkoxyl radical eliminating capacities (L-AREC) of these lipophilic antioxidants were determined using TRX as a standard. The evaluated L-AREC values are directly connected to the second order rate constants for the RO• radical induced hydrogen atom abstractions from the hydroxyl groups of the phenolic antioxidants, as well as from the allylic methylene groups of unsaturated fatty acids. The L-AREC values estimated by LFI-ESR method are concluded to be a practical and reliable indicator that reflect the inhibiting abilities of lipophilic antioxidants towards the radical chain reaction involved in the autoxidation processes of unsaturated fatty acids.

A New Tocopherol Derivative and Cytotoxicity from the Leaves of Dalbergia velutina

A new tocopherol derivative, named (+)-α-tocuspirone (1), along with eleven known compounds, including six tocopherol derivatives (2–7) and five triterpenes (8–12) were isolated from the leaves of Dalbergia velutina. Their structures were determined by spectroscopic analysis especially NMR spectroscopy. The absolute configurations of 1 and 2 were assigned by NOESY experiments and ECD calculations. All isolated compounds were evaluated for their cytotoxicity against five cancer cell lines (KB, HeLa S-3, HT-29, MCF-7 and HepG-2). Dioslupecin A (10) showed potent cytotoxicity against all the five cancer cell lines with IC50 values in the range of 0.28–2.05 μM. In addition, caffeoxylupeol (12) showed potent cytotoxicity against KB cell with an IC50 value of 2.28 μM.

The Benefits of Ultra-High-Performance Supercritical Fluid Chromatography in Determination of Lipophilic Vitamins in Dietary Supplements

Nine tocopherol derivatives including four tocopherols, four tocotrienols, and one esterified form of α-tocopherol acetate were analyzed using ultra-high-performance supercritical fluid chromatography (UHPSFC) with diode array detection. The separation was carried out on BEH 2-EP column using shallow gradient elution of 1–4% methanol and CO2 in 5 min. Complementary ultra-high-performance liquid chromatography method was developed using Ascentis Express F5 core–shell stationary phase and isocratic elution with 75% acetonitrile/methanol (1:1) and 25% water. This separation took 12 min that is the shortest liquid chromatography run in analysis of all tocopherol derivatives reported so far. However, our UHPSFC method resulted in more than two times faster analysis, and allowed direct injection of heptane solutions and extracts from liquid–liquid extraction. These features made UHPSFC a method of choice for subsequent analysis of dietary supplements containing different forms of vitamin E. Sample preparation methods were optimized for individual dosage forms of drops, capsules, tablets, and granulate.

Phytochemical characterization of the Chinese endemic species Stemona mairei and five other Stemona species

Comparative HPLC-PDA analyses of methanolic root extracts of the almost unstudied Chinese endemic species Stemona mairei, collected from nine locations throughout its natural habitat in northern Yunnan, led to the identification of the pyrrolo[1,2-α]azepine-type alkaloid protostemonine (1) as the main alkaloid and 3,4-dehydro-δ-tocopherol (9) as the main tocopherol derivative. Analysis of the five further Chinese Stemona species S. sessilifolia, S. japonica, S. parviflora and S. shandongensis, collected in adjacent locations, resulted in identification of eight Stemona alkaloids, with seven of them possibly derived from 1. Additionally, the presence of three tocopherols was confirmed co-chromatographically with authentic samples. From S. shandongensis, the alkaloids stemocochinin (7) and croomine (8) were isolated and their structures confirmed by NMR and MS analyses. Additionally, the quantitative content of protostemonine (1) and the tocopherols 9 and 10 present in extracts were assessed. Concerning the tocopherols, S. mairei differs by the occurrence of chromenol derivatives from the other species which accumulate both chromenol and chromanol derivatives. Furthermore, the root extracts of S. mairei exhibited nematicidal activities against Panagrellus redivivus. These results are briefly discussed in a biological and chemotaxonomic context, respectively.

Allergenic Ingredients in Facial Wet Wipes.

Allergic contact dermatitis commonly occurs on the face. Facial cleansing wipes may be an underrecognized source of allergens. The aim of this study was to determine the frequency of potentially allergenic ingredients in facial wet wipes. Ingredient lists from name brand and generic facial wipes from 4 large retailers were analyzed. In the 178 facial wipes examined, a total of 485 ingredients were identified (average, 16.7 ingredients per wipe). Excluding botanicals, the top 15 potentially allergenic ingredients were glycerin (64.0%), fragrance (63.5%), phenoxyethanol (53.9%), citric acid (51.1%), disodium EDTA (44.4%), sorbic acid derivatives (39.3%), tocopherol derivatives (38.8%), polyethylene glycol derivatives (32.6%), glyceryl stearate (31.5%), sodium citrate (29.8%), glucosides (27.5%), cetearyl alcohol (25.8%), propylene glycol (25.3%), sodium benzoate (24.2%), and ceteareth-20 (23.6%)/parabens (23.6%). Of note, methylisothiazolinone (2.2%) and methylchloroisothiazolinone (1.1%) were uncommon. The top potential allergens of botanical origin included Aloe barbadensis (41.0%), chamomile extracts (27.0%), tea extracts (21.3%), Cucumis sativus (20.2%), and Hamamelis virginiana (10.7%). Many potential allergens are present in facial wet wipes, including fragrances, preservatives, botanicals, glucosides, and propylene glycol.

A new lipid excipient, phosphorylated tocopherol mixture, TPM enhances the solubilisation and oral bioavailability of poorly water soluble CoQ10 in a lipid formulation

Phosphorylated tocopherols are a new class of lipid excipients that have demonstrated potential in pharmaceutical applications. Their ability to solubilise poorly water soluble drugs indicates their potential utility in improving bioavailability of drugs where solubility limits their bioavailability. In this study a commercial mixture of phosphorylated tocopherols, TPM was combined with medium chain triglyceride (MCT) as a formulation for CoQ10, and in vitro and in vivo performance compared to the effect of addition of alternative tocopherol-based excipients. In in vitro digestion experiments, CoQ10 was poorly solubilised in the digesting MCT as anticipated. Addition of TPM facilitated the enhanced solubilisation of CoQ10 as did vitamin E TPGS (TPGS). Other tocopherol derivatives (tocopherol acetate, tocopherol) were less effective at solubilising the active during the digestion process. The trends in in vitro solubilisation were conserved in the in vivo bioavailability of CoQ10 after oral administration to rats, with TPM and TPGS formulations providing approximately double the exposure of MCT alone, while the addition of the other tocopherol derivatives reduced the overall exposure. Collectively, the results indicate potential of TPM as a new solubilising excipient for use in oral drug delivery for poorly water soluble drugs.

Nutritional metabolomics and breast cancer risk in a prospective study

Background: The epidemiologic evidence for associations between dietary factors and breast cancer is weak and etiologic mechanisms are often unclear. Exploring the role of dietary biomarkers with metabolomics can potentially facilitate objective dietary characterization, mitigate errors related to self-reported diet, agnostically test metabolic pathways, and identify mechanistic mediators.Objective: The aim of this study was to evaluate associations of diet-related metabolites with the risk of breast cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.Design: We examined prediagnostic serum concentrations of diet-related metabolites in a nested case-control study in 621 postmenopausal invasive breast cancer cases and 621 matched controls in the multicenter PLCO cohort. We calculated partial Pearson correlations between 617 metabolites and 55 foods, food groups, and vitamin supplements on the basis of the 2015 Dietary Guidelines for Americans and derived from a 137-item self-administered food-frequency questionnaire. Diet-related metabolites (P-correlation < 1.47 × 10-6) were evaluated in breast cancer analyses. ORs for the 90th compared with the 10th percentile were calculated by using conditional logistic regression, with body mass index, physical inactivity, other breast cancer risk factors, and caloric intake controlled for (false discovery rate <0.2).Results: Of 113 diet-related metabolites, 3 were associated with overall breast cancer risk (621 cases): caprate (10:0), a saturated fatty acid (OR: 1.77; 95% CI = 1.28, 2.43); γ-carboxyethyl hydrochroman (γ-CEHC), a vitamin E (γ-tocopherol) derivative (OR: 1.64; 95% CI: 1.18, 2.28); and 4-androsten-3β,17β-diol-monosulfate (1), an androgen (OR: 1.61; 95% CI: 1.20, 2.16). Nineteen metabolites were significantly associated with estrogen receptor (ER)-positive (ER+) breast cancer (418 cases): 12 alcohol-associated metabolites, including 7 androgens and α-hydroxyisovalerate (OR: 2.23; 95% CI: 1.50, 3.32); 3 vitamin E (tocopherol) derivatives (e.g., γ-CEHC; OR: 1.80; 95% CI: 1.20, 2.70); butter-associated caprate (10:0) (OR: 1.81; 95% CI: 1.23, 2.67); and fried food-associated 2-hydroxyoctanoate (OR: 1.46; 95% CI: 1.03, 2.07). No metabolites were significantly associated with ER-negative breast cancer (144 cases).Conclusions: Prediagnostic serum concentrations of metabolites related to alcohol, vitamin E, and animal fats were moderately strongly associated with ER+ breast cancer risk. Our findings show how nutritional metabolomics might identify diet-related exposures that modulate cancer risk. This trial was registered at clinicaltrials.gov as NCT00339495.

Enhanced antitumor activity of surface-modified iron oxide nanoparticles and an α-tocopherol derivative in a rat model of mammary gland carcinosarcoma.

Maghemite (γ-Fe2O3) nanoparticles were obtained by coprecipitation of ferrous and ferric salts in an alkaline medium followed by oxidation; the nanoparticles were coated with poly(N,N-dimethylacrylamide) (PDMA) and characterized by transmission electron microscopy, attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering, thermogravimetric and elemental analyses, and magnetic measurements in terms of particle morphology, size, polydispersity, amount of coating, and magnetization, respectively. The effects of α-tocopherol (Toc) and its phenolic (Toc-6-OH) and acetate (Toc-6-Ac) derivatives on Fe2+ release from γ-Fe2O3@PDMA, as well as from γ-Fe2O3 and CuFe2O4 nanoparticles (controls), were examined in vitro using 1,10-phenanthroline. The presence of tocopherols enhanced spontaneous Fe2+ release from nanoparticles, with Toc-6-OH exhibiting more activity than neat Toc. All of the nanoparticles tested were found to initiate blood lipid oxidation in a concentration-dependent manner, as determined by analysis of 2-thiobarbituric acid reactive species. Wistar rats with Walker-256 carcinosarcoma (a model of mammary gland carcinosarcoma) received Toc-6-Ac, magnetic nanoparticles, or their combination per os, and the antitumor activity of each treatment was determined in vivo. γ-Fe2O3@PDMA nanoparticles exhibited increased antitumor activity compared to both commercial CuFe2O4 particles and the antitumor drug doxorubicin. Moreover, increased antitumor activity was observed after combined administration of γ-Fe2O3@PDMA nanoparticles and Toc-6-Ac; however, levels of bilirubin, aspartate aminotransferase, and white bloods normalized and did not differ from those of the intact controls. The antitumor activity of the γ-Fe2O3 nanoparticles strongly correlated with Fe2+ release from the nanoparticles but not with nanoparticle-initiated lipid peroxidation in vitro.