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

Abu-Fayyad, Ahmed; Behery, Fathy A.; Sallam, Asmaa A.; Alqahtani, Saeed; Ebrahim, Hassan Y.; Sayed, Khalid A. El; Kaddoumi, Amal; Sylvester, Paul W.; Carroll, Jennifer L.; Cardelli, James A.; Nazzal, Sami

doi:10.1016/j.ejpb.2015.07.022

Cited by 27 publications

(31 citation statements)

References 46 publications

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“…5), respectively. The melting points of mPEG 1000 conjugates was comparable to the reported melting point of the commercial vitamin E TPGS (41 °C) (Abu-Fayyad et al, 2015) and the melting point of mPEG 1000 (37–40 °C) (I Sciencelab.com, 2005). The mPEG 350 conjugates were liquid/semi-solid at room temperature and therefore their melting point was not measured.…”

Section: Resultssupporting

confidence: 73%

“…Two molecular weight variants of mPEG were used to accomplish this goal; mPEG 350 and mPEG 1000; (2) characterize the PEG conjugates by HPLC, 1 H NMR, mass spectroscopy, and thermal analysis; and to analyze the self-assembled micelles of the PEGylated isomers in water for particle size, zeta potential, critical micelle concentration, and by Cryo-TEM microscopy; (3) test the inhibitory effect of the PEGylated vitamin E isomers on P-glycoprotein ATPase activity; and (4) evaluate the in-vitro anticancer activity of the conjugates against the following panel of cell lines: breast cancer (MCF-7 and MDA-MB-231), pancreatic cancer (AsPC-1, BxPC-3, MIA-PaCa-2 and PANC-1), human epithelial mammary gland (hTERT-HME), human pancreatic duct (hTERT-HPNE-1), and the non-tumorigenic human mammary gland (MCF-10). To the best of our knowledge this work, along with our previous study (Abu-Fayyad et al, 2015), mark the first report on the full characterization and in-vitro cytotoxicity evaluation of PEGylated tocopherol and tocotrienol isomers of vitamin E.…”

Section: Introductionmentioning

confidence: 83%

“…The method for the synthesis of α-T succinate, α-T 3 succinate, γ-T 3 succinate and δ-T 3 succinate was adapted from our previous work (Abu-Fayyad et al, 2015). The general reaction scheme is outlined in Fig.…”

Section: Methodsmentioning

confidence: 99%

“…The synthesis method was modified from Lipshutz et al (2011) and Abu-Fayyad et al (2015) using terminally methylated PEGs with molecular weights of approximately 350 (mPEG 350) and 1000 (mPEG1000). The reaction scheme is outlined in Fig.…”

Section: Methodsmentioning

confidence: 99%

“…The CMC of the PEGylated isomers in water was determined using pyrene as a fluorescence probe as previously reported (Abu-Fayyad et al, 2015). Before analysis, 0.05 to 0.67 mg/ml stock solutions of α-TPGS 350, α-T 3 PGS 350, γ-T 3 PGS 350 and δ-T 3 PGS 350, and 0.02 to 1.00 mg/ml sock solutions of α-TPGS 1000, α-T 3 PGS 1000, γ-T 3 PGS 1000 and δ-T 3 PGS 1000 were prepared by dissolving the conjugates in water.…”

Section: Methodsmentioning

confidence: 99%

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Synthesis, characterization, and in-vitro antitumor activity of the polyethylene glycol (350 and 1000) succinate derivatives of the tocopherol and tocotrienol isomers of Vitamin E

Abu-Fayyad

Nazzal

2017

International Journal of Pharmaceutics

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Vitamin E refers to a group of saturated tocopherol (T) isomers and the biologically more active unsaturated tocotrienol (T3) isomers. PEGylated α-tocopherol, commercially known as Vitamin E TPGS, has been used as an emulsifier and therapeutic agent for children with vitamin E deficiency. Limited information, however, is available about the PEG conjugates of the tocotrienol isomers of vitamin E. The current work was therefore undertaken to synthesize and characterize the water soluble polyethylene glycol (PEG 350 and 1000) derivatives of T and T3. Yield and the identity of the synthesized products were confirmed by 1H NMR, mass spectroscopy, HPLC, and thermal analysis. The self-assembly of the PEGylated vitamin E isomers in water at critical micelle concentrations (CMC) was further confirmed by size, zeta, and Cryo-TEM image analysis. While stable at pH 7.4, PEG conjugates were found to rapidly hydrolyze at pH 1.2. Our data showed that PEGylated T3 isomers were significantly more active as inhibitors for P-glycoprotein than PEGylated T. The in vitro cytotoxicity of the conjugates was also tested against a large panel of normal and tumorigenic cells. Of the conjugates, γ-T3PGS 1000 and δ-T3PGS 1000 were found to have the least toxicity against non-tumorigenic breast and pancreatic cell lines, which may be advantageous for its use as functional excipients in drug delivery. The results from the current work have demonstrated the feasibility of synthesizing PEGylated conjugates of vitamin E isomers and highlighted the potential use of these conjugates in drug delivery as functional and safer excipients especially for γ-T3PGS 1000 and δ-T3PGS 1000 conjugate.

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Section: Resultssupporting

confidence: 73%

Section: Introductionmentioning

confidence: 83%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Synthesis, characterization, and in-vitro antitumor activity of the polyethylene glycol (350 and 1000) succinate derivatives of the tocopherol and tocotrienol isomers of Vitamin E

Abu-Fayyad

Nazzal

2017

International Journal of Pharmaceutics

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Biodegradable and Functional Synthetic Polymers in Nanomedicine: Controlled and Targeted Bioactive Molecule Release

Guo

Chan

Chen

2020

Reactive and Functional Polymers Volume One

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Extraction of Vitamin E Isomers from Palm Oil: Methodology, Characterization, and in Vitro Anti‐Tumor Activity

Abu-Fayyad

Nazzal

2017

J Americ Oil Chem Soc

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Vitamin E refers to a family of eight tocopherols (T) and tocotrienol (T3) isomers. Due to the unique pharmacological and anticancer activity of the individual isomers, there is a need to extract and separate the individual T3 isomers from T/T3 rich fractions of palm oil. The objective of the present study was to present a detailed protocol for the extraction of gram quantities of vitamin E isomers from a T3 rich fraction (Tocotrol™) that was obtained from palm oil, by column chromatography using a binary hexane:EtOAc (1–12%) phase system. The chemical integrity and identity of the extracted isomers was confirmed by TLC, HPLC, 1H‐NMR, and Raman analysis. To evaluate their anticancer activity, vitamin E isomers were first entrapped into nanoemulsions and then tested against a panel of breast and pancreatic cancer cell lines. Nanoemulsions were prepared by the solvent evaporation technique. They had an average droplet size between 156–200 nm. In confirmation to what has been reported in the literature, γ‐T3 and δ‐T3 isomers were found to be significantly more active against tumor cells than the α‐T and α‐T3 isomers. The current study has demonstrated the feasibility of extracting the individual vitamin E isomers at high yields from natural sources while maintaining their chemical integrity and pharmacological activity.

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

Cited by 27 publications

References 46 publications

Synthesis, characterization, and in-vitro antitumor activity of the polyethylene glycol (350 and 1000) succinate derivatives of the tocopherol and tocotrienol isomers of Vitamin E

Synthesis, characterization, and in-vitro antitumor activity of the polyethylene glycol (350 and 1000) succinate derivatives of the tocopherol and tocotrienol isomers of Vitamin E

Biodegradable and Functional Synthetic Polymers in Nanomedicine: Controlled and Targeted Bioactive Molecule Release

Extraction of Vitamin E Isomers from Palm Oil: Methodology, Characterization, and in Vitro Anti‐Tumor Activity

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