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

Abstract

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.

Physicochemical Characterization of Ferrocifen Lipid Nanocapsules: Customized Drug Delivery Systems Guided by the Molecular Structure

“…Moreover, no difference in IC 50 was observed when different ferrocifens were free or encapsulated in LNCs, confirming results from the literature that LNCs did not alter the ferrocifen efficacy. ,, Moreover, it was possible to distinguish two slopes on cell viability depending on the ferrocifen concentration. This could be associated with a senescence mechanism at low concentrations, as already described for P722 , and also for the ansa-ferrocifen DP1 , followed by an apoptotic mechanism at higher concentrations . Finally, chemical modification performed on the initial P722 did not significantly hamper its efficiency.…”

“…All studies previously performed on ferrocifen–LNCs showed only the formation of a suspension, compatible with an intravenous administration route, with promising results on several cancers. ,,, For the P769 –LNC gel, the use as a local therapy to treat glioblastoma after tumor resection could be imagined as ferrocifens have already shown efficacy against this cancer. − Indeed, Vessières et al showed a large heterogeneity of response to P722 on patient-derived cell-line glioblastoma depending on transcriptomic subtypes . A more recent study also highlighted the efficiency of P722 complexed with cyclodextrins on glioblastomas . Moreover, P769 was tested on the U87MG glioblastoma cell line, with or without LNCs, and the IC 50 values obtained were 67 and 46 nM, respectively, close to the 27 nM obtained with P722 alone, after 96 h of treatment .…”

“…To the best of our knowledge, it is the first time that a structure–drug delivery system relationship has been demonstrated for ferrocifens. Knowing that ovarian cancer metastases mostly in the peritoneal cavity, together with the remarkable in vivo efficacy on several cancers of P722 (glioblastoma, metastatic melanoma, and ovarian cancer), we can see new opportunities for the use of P769 –LNC gels as local therapies to combat glioblastomas or peritoneal metastatic ovarian cancers.…”

“…They are composed of a liquid oily core and a polyethylene glycol (PEG) hydroxystearate surfactant shell. Recent studies have highlighted the successful encapsulation of diphenol P722 in LNCs, with promising in vivo results on metastatic melanoma, glioblastoma, and epithelial ovarian cancer. − However, compared to other ferrocifens, drug loading (DL) of this compound in LNCs remains particularly weak.…”

Unravelling the Role of Uncommon Hydrogen Bonds in Cyclodextrin Ferrociphenol Supramolecular Complexes: A Computational Modelling and Experimental Study

“…SuccFerr was recently formulated with various nanocapsules in its diphenol form, or to increase its lipophilicity and the load in lipid nanocapsules, as monoacetate [22] or diacetate [22][23][24], with or without the unexpected formation of a gel [22]. It was recently formulated with randomly methylated cyclodextrins (RAMEβCDs) and tested in vivo without noticeable adverse toxicity [25], but this last complexation has yet to be analyzed more finely by modelling and laboratory experiments.…”