We have shown that the natural compound (Z)-Butylidenephthalide (Bdph), isolated from the chloroform extract of Angelica sinensis, has antitumor effects. Because of the limitation of the blood-brain barrier, the (Z)-Butylidenephthalide dosage required for treatment of glioma is relatively high. To solve this problem, we developed a local-release system with (Z)-Butylidenephthalide incorporated into a biodegradable polyanhydride material, p(CPP-SA; Bdph-Wafer), and investigated its antitumor effects.
METHODS AND RESULTS:
On the basis of in vitro release kinetics, we demonstrated that the (Z)-Butylidenephthalide-Wafer released 50% of the available (Z)-Butylidenephthalide by the sixth day, and the release reached a plateau phase (90% of (Z)-Butylidenephthalide) by the 30th day. To investigate the in situ antitumor effects of the Bdph-Wafer on glioblastoma multiforme (GBM), we used 2 xenograft animal models-F344 rats (for rat GBM) and nude mice (for human GBM)-which were injected with RG2 and DBTRG-05MG cells, respectively, for tumor formation and subsequently treated subcutaneously with (Z)-Butylidenephthalide-Wafers. We observed a significant inhibitory effect on tumor growth, with no significant adverse effects on the rodents. Moreover, we demonstrated that the antitumor effect of (Z)-Butylidenephthalide on RG2 cells was via the PKC pathway, which upregulated Nurr77 and promoted its translocation from the nucleus to the cytoplasm. Finally, to study the effect of the interstitial administration of z-butylidenephthalide in cranial brain tumor, Bdph-Wafers were surgically placed in FGF-SV40 transgenic mice. Our (Z)-Butylidenephthalide-Wafer significantly reduced tumor size in a dose-dependent manner.
CONCLUSIONS:
In summary, our study showed that p(CPP-SA) containing (Z)-Butylidenephthalide delivered a sufficient concentration of Bdph to the tumor site and effectively inhibited the tumor growth in the glioma. |
Cell. 2018 Jan 11;172(1-2):249-261.e12. doi: 10.1016/j.cell.2017.12.019.IF=36.216(2019)
Cell Metab. 2020 Mar 3;31(3):534-548.e5. doi: 10.1016/j.cmet.2020.01.002.IF=22.415(2019)
Mol Cell. 2017 Nov 16;68(4):673-685.e6. doi: 10.1016/j.molcel.2017.10.022.IF=14.548(2019)
ACS Nano. 2018 Apr 24;12(4): 3385-3396. doi: 10.1021/acsnano.7b08969.IF=13.903(2019)
Nature Plants. 2016 Dec 22;3: 16206. doi: 10.1038/nplants.2016.205.IF=13.297(2019)
Sci Adv. 2018 Oct 24;4(10): eaat6994. doi: 10.1126/sciadv.aat6994.IF=12.804(2019)