Dataset Information

Biological fate and interaction with cytochromes P450 of the nanocarrier material, d-α-tocopheryl polyethylene glycol 1000 succinate.

ABSTRACT: d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS, also known as vitamin E-TPGS) is a biodegradable amphiphilic polymer prepared by esterification of vitamin E with polyethylene glycol (PEG) 1000. It is approved by the US Food and Drug Administration (FDA) and has found wide application in nanocarrier drug delivery systems (NDDS). Fully characterizing the in vivo fate and pharmacokinetic behavior of TPGS is important to promote the further development of TPGS-based NDDS. However, to date, a bioassay for the simultaneous quantitation of TPGS and its metabolite, PEG1000, has not been reported. In the present study, we developed such an innovative bioassay and used it to investigate the pharmacokinetics, tissue distribution and excretion of TPGS and PEG1000 in rat after oral and intravenous dosing. In addition, we evaluated the interaction of TPGS with cytochromes P450 (CYP450s) in human liver microsomes. The results show that TPGS is poorly absorbed after oral administration with very low bioavailability and that, after intravenous administration, TPGS and PEG1000 are mainly distributed to the spleen, liver, lung and kidney before both being slowly eliminated in urine and feces as PEG1000. In vitro studies show the inhibition of human CYP450 enzymes by TPGS is limited to a weak inhibition of CYP3A4. Overall, our results provide a clear picture of the in vivo fate of TPGS which will be useful in evaluating the safety of TPGS-based NDDS in clinical use and in promoting their further development.

SUBMITTER: Ren T

PROVIDER: S-EPMC9293673 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundCombination therapy employing siRNAs and antitumor drugs is a promising method for the treatment of solid tumors. However, regarding combined treatments involving siRNAs and chemotherapeutic reagents, most prior research has focused on the enhanced cytotoxicity against tumor cells conferred by downregulation of the targeted protein.PurposeWe developed D-?-tocopherol polyethylene glycol 1000 succinate (TPGS)-modified cationic liposomes (LPs) to simultaneously deliver doxorubicin (Dox) and the Bcl-2 siRNA (siBcl-2) for synergistic chemotherapy. The co-loading of siBcl-2 onto the Dox-loaded cationic LPs (siBcl-2/Dox-TPGS-LPs) could promote cellular uptake, cytotoxicity against 3D H22 tumor spheroids, circulation in the blood, drug accumulation at tumor sites, and synergistic chemotherapy in vivo.MethodsThe siBcl-2/Dox-TPGS-LPs were constructed by co-loading siBcl-2 onto the Dox-loaded TPGS-modified cationic LPs (Dox-TPGS-LPs), and Dox entrapment into the LPs was achieved using an ammonium sulfate gradient method. The antitumor effects of siBcl-2/Dox-TPGS-LPs were studied in murine hepatic carcinoma H22 cells, 3D H22 tumor spheroids, and H22 tumor-bearing mice.ResultsDynamic light scattering technique and transmission electron microscopy images revealed that siBcl-2 loaded onto the Dox-TPGS-LPs formed a prominent corona at an nitrogen to phosphorus (N/P) ratio of 4:1, resulting in particle size increase from 155 to 210 nm and a weak positive zeta potential (+12.5 mV). The siBcl-2/Dox-TPGS-LPs enhanced the cellular uptake of Dox, promoted toxicity against 3D H22 tumor spheroids via tumor priming, prolonged Dox circulation in the blood, and increased accumulation of Dox at tumor sites, thereby enhancing the cytotoxicity of Dox in vitro and its chemotherapeutic efficacy in vivo.ConclusionThe siBcl-2/Dox-TPGS-LPs demonstrated a strong potential for application in synergistic chemotherapy. The co-loading of siRNAs both sensitized cells toward antitumor drugs by downregulating the expression level of a specific protein and influenced the pharmacokinetic behavior of the co-delivery system in vitro and in vivo.

Dataset Information

Biological fate and interaction with cytochromes P450 of the nanocarrier material, d-α-tocopheryl polyethylene glycol 1000 succinate.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets