Block copolymer micelles are water-soluble biocompatible nanocontainers with great potential for delivering hydrophobic drugs. An understanding of their cellular distribution is essential to achieving selective delivery of drugs at the subcellular level. Triple-labeling confocal microscopy in live cells revealed the localization of micelles in several cytoplasmic organelles, including mitochondria, but not in the nucleus. Moreover, micelles change the cellular distribution of and increase the amount of the agent delivered to the cells. These micelles may thus be worth exploring for their potential to selectively deliver drugs to specified subcellular targets.

Purpose Hepatocellular carcinoma (HCC) is a heterogeneous cancer with active Wnt-signaling. Underlying biological mechanisms remain unclear and no drug targeting this pathway has been approved to date. We aimed to characterize Wnt-pathway aberrations in HCC patients, and to investigate sorafenib as a potential Wnt modulator in experimental models of liver cancer. Experimental Design The Wnt-pathway was assessed using mRNA (642 HCCs and 21 liver cancer cell lines) and miRNA expression data (89 HCCs), immunohistochemistry (108 HCCs) and CTNNB1-mutation data (91 HCCs). Effects of sorafenib on Wnt-signaling were evaluated in four liver cancer cell lines with active Wnt signaling and a tumor xenograft model. Results Evidence for Wnt activation was observed for 315 (49.1%) cases, and was further classified as CTNNB1-class [138 cases (21.5%)] or Wnt-TGFβ-class [177 cases (27.6%)]. CTNNB1-class was characterized by up-regulation of liver-specific Wnt-targets, nuclear β-catenin and glutamine-synthetase immunostaining, and enrichment of CTNNB1-mutation-signature, while Wnt-TGFβ-class was characterized by dysregulation of classical Wnt-targets and the absence of nuclear β-catenin. Sorafenib decreased Wnt-signaling and β-catenin protein in HepG2 (CTNNB1-class), SNU387 (Wnt-TGFβ-class), SNU398 (CTNNB1-mutation) and Huh7 (Lithium-chloride-pathway activation) cell lines. Additionally, sorafenib attenuated expression of liver-related Wnt-targets GLUL, LGR5, and TBX3. The suppressive effect on CTNNB1-class-specific Wnt-pathway activation was validated in vivo using HepG2 xenografts in nude mice, accompanied by decreased tumor volume and increased survival of treated animals. Conclusions Distinct dysregulation of Wnt-pathway constituents characterize two different Wnt-related molecular classes (CTNNB1 and Wnt-TGFβ), accounting for half of all HCC patients. Sorafenib modulates β-catenin/Wnt-signaling in experimental models that harbor the CTNNB1-class-signature.