4.6 Article

Succinimido-Ferrocidiphenol Complexed with Cyclodextrins Inhibits Glioblastoma Tumor Growth In Vitro and In Vivo without Noticeable Adverse Toxicity

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MOLECULES
卷 27, 期 14, 页码 -

出版社

MDPI
DOI: 10.3390/molecules27144651

关键词

ferrocenyl tamoxifen derivatives; cyclodextrin; glioblastoma; anticancer drug

资金

  1. Agence Nationale de la Recherche
  2. University of Carthage (Tunisia)

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SuccFerr has remarkable antiproliferative effects and shows potential for clinical research. The water insolubility of SuccFerr is solved by complexation with RAMEssCDs, enabling in vivo experiments. The compound does not exhibit toxic effects on organs in vivo, and it can halt tumor progression in rats with xenografted tumors, possibly through an immunological defense response.
SuccFerr (N-[4-ferrocenyl,5-5-bis (4-hydroxyphenyl)-pent-4-enyl]-succinimide) has remarkable antiproliferative effects in vitro, attributed to the formation of a stabilized quinone methide. The present article reports in vivo results for a possible preclinical study. SuccFerr is lipophilic and insoluble in water, so the development of a formulation to obviate this inconvenience was necessary. This was achieved by complexation with randomly methylated cyclodextrins (RAMEssCDs). This supramolecular water-soluble system allowed the in vivo experiments below to proceed. Application of SuccFerr on the glioblastoma cancer cell line U87 indicates that it affects the cellular cycle by inducing a blockade at G0/G1 phase, linked to apoptosis, and another one at the S phase, associated with senescence. Using healthy Fischer rats, we show that both intravenous and subcutaneous SuccFerr: RAMEssCD administration at 5 mg/kg lacks toxic effects on several organs. To reach lethality, doses higher than 200 mg/kg need to be administered. These results prompted us to perform an ectopic in vivo study at 1 mg/kg i.v. ferrocidiphenol SuccFerr using F98 cells xenografted in rats. Halting of cancer progression was observed after six days of injection, associated with an immunological defense response linked to the active principle. These results demonstrate that the properties of the selected ferrocidiphenol SuccFerr transfer successfully to in vivo conditions, leading to interesting therapeutic perspectives based on this chemistry.

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