Abstract
Following our previous work on the antitumor activity of acetylated flavonosides, a new acetylated xanthonoside, 3,6-bis(2,3,4,6-tetra-O-acetyl-β-glucopyranosyl)xanthone (2), was synthesized and discovered as a potent inhibitor of tumor cell growth. The synthesis involved the glycosylation of 3,6-di-hydroxyxanthone (1) with acetobromo-α-d-glucose. Glycosylation with silver carbonate decreased the amount of glucose donor needed, comparative to the biphasic glycosylation. Xanthone 2 showed a potent anti-growth activity, with GI50 < 1 μM, in human cell lines of breast, lung, and glioblastoma cancers. Current treatment for invasive brain glioma is still inadequate and new agents against glioblastoma with high brain permeability are urgently needed. To overcome these issues, xanthone 2 was encapsulated in a liposome. To increase the well-known low stability of these drug carriers, a proliposome formulation was developed using the spray drying method. Both formulations were characterized and compared regarding three months stability and in vitro anti-growth activity. While the proliposome formulation showed significantly higher stability, it was at the expense of losing its biocompatibility as a drug carrier in higher concentrations. More importantly, the new xanthone 2 was still able to inhibit the growth of glioblastoma cells after liposome formulation.
Highlights
Current treatment for invasive brain glioma is still inadequate, and prognosis upon diagnosis tends to be very poor
Glycosylation was performed according to according to previously described procedures [36] by biphasic Michael reaction—phase transfer previously described procedures [36] by biphasic Michael reaction—phase transfer catalyzed (PTC)
A potent antitumor synthetic xanthone derivative was synthesized and proliposomes and liposomes have been developed as drug carriers
Summary
Current treatment for invasive brain glioma is still inadequate, and prognosis upon diagnosis tends to be very poor. Conventional surgical methods and/or radiotherapy alone cannot eliminate cancer cells from the brain, and the relapse is, most of the time, inevitable [3]. Temozolomide, an alkylating agent, remains the standard-of-care in glioma chemotherapy. Chemotherapy for gliomas is difficult due to two major obstacles: The blood-brain barrier (BBB) and the heterogeneity of the brain cancer [4]. Substitution of the amide group of temozolomide for a methylketone increased brain permeability with 69% entering the central nervous system compared with just 8% for temozolomide and produced a more effective compound when tested in mice [5]. Temozolomide was recently encapsulated in liposomes for brain tumor treatment [6]
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