Novel hydrophilic camptothecin derivatives conjugated to branched glycerol trimer suppress tumor growth without causing diarrhea in murine xenograft models of human lung cancer.

Camptothecin possesses broad antitumor spectra on various cancers. In spite of its marked tumor suppressing potency, camptothecin is too hydrophobic to be solved in water, and therefore it is not currently in clinical use. CPT-11 (irinotecan) is one of the hydrophilic analogs of camptothecin and widely prescribed. However, its water-solubility is still low and furthermore, CPT-11 evokes severe diarrhea. Therefore, we designed and synthesized novel highly hydrophilic camptothecin-derivatives by conjugating SN38 with branched glycerol trimer (SN38-BGL), which we have been developing as a unique strategy to endow hydrophobic molecule with much hydrophilicity, to maximize the benefit of CPT-11 and minimize the adverse effects. The SN38-BGLs exhibited equivalent or slightly stronger tumor suppressing effects in murine xenograft human lung cancer models compared to CPT-11. However, neither early- nor late-onset diarrhea was observed when SN38-BGL was administrated. Heights of villi in jejunum and ileum were bigger than those from CPT-11-treated mice, indicating that SN38-BGL is less harmful than CPT-11. Ex vivo digestion by liver microsome did not yield SN38 but a couple of other molecules against our expectations, which suggests involvement of other active metabolites than SN38 and may explain the differences. Hence, SN38-BGLs can be novel hydrophilic camptothecin-derivatives without causing severe diarrhea.