snx-2112 and Breast-Neoplasms

Systemic delivery of amphiphobic drugs (insoluble in both water and oil) represents a formidable challenge in drug delivery. This work aimed to engineer a functional mesoporous carbon material to efficiently load SNX-2112, an amphiphobic anticancer agent, and to evaluate its performance in tumor-targeting delivery. Hydrothermal reaction combined with high-temperature activation was used to fabricate glucose-based mesoporous carbon nanospheres (MCNs). SNX-2112-loaded MCNs stabilized by phospholipid (SN-PMCNs) were prepared by the absorption/solvent diffusion/high-pressure homogenization method. The obtained SN-PMCNs were 180nm around in particle size, showing a high drug load (42.7%) and acceptable physical stability. SN-PMCNs demonstrated an enhanced in vitro antitumor effect and increased uptake into cancer cells in comparison with the formulation of SNX-2112 solution (SN-Sol). The in vivo antitumor effect and biodistribution in 4T1 xenograft tumor mice, a breast cancer model, were also significantly improved through SN-PMCNs. It was shown that specific clathrin-dependent and nonspecific caveolae-dependent endocytosis were involved in the cellular trafficking of SN-PMCNs. Glucose transporter-mediated transport, prolonged body residence time and improved biodistribution via EPR effect were the main mechanisms of enhanced antitumor effect. SN-PMCNs have presented excellent tumor targeting properties and should be a promising carrier to address the systemic delivery of SNX-2112.

Topics: Adsorption; Animals; Antineoplastic Agents; Breast Neoplasms; Carbon; Cell Survival; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Drug Carriers; Endocytosis; Female; Glucose Transport Proteins, Facilitative; Hep G2 Cells; Heterocyclic Compounds, 4 or More Rings; HSP90 Heat-Shock Proteins; Humans; MCF-7 Cells; Mice, Inbred BALB C; Nanoconjugates; Nanomedicine; Phospholipids; Porosity; Solubility; Technology, Pharmaceutical; Tissue Distribution; Tumor Burden; Xenograft Model Antitumor Assays

SNX-2112 is a heat shock protein 90 (Hsp90) inhibitor with anticancer properties currently in clinical trials. This study investigated the effects of SNX-2112 on inhibition of cell growth, the cell cycle, and apoptosis in MCF-7 human breast cancer cells, in addition to the various molecular mechanisms. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis suggest that SNX-2112 inhibits cell growth in a time- and dose-dependent manner more potently than 17-(allylamino)-17-demethoxygeldanmycin (17-AAG), a traditional Hsp90 inhibitor, probably as a result of cell-cycle arrest at the G2/M phase and the induction of apoptosis. Downregulation of Bcl-2 and Bcl-xL, upregulation of Bax, cleavage of caspase-9 and poly (ADP-ribose) polymerase (PARP), and degradation of the breast cancer-related Hsp90 client proteins human epidermal growth factor receptor-2 (HER2), Akt, Raf-1, and nuclear factor kappa-B kinase (IKK) were observed in SNX-2112 treated cells by Western blot assay. These findings suggest that the molecular mechanisms of cell-growth inhibition by SNX-2112 involve activation of the mitochondrial apoptotic pathway and the degradation of breast cancer-related proteins.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Benzoquinones; Blotting, Western; Breast Neoplasms; Caspase 9; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 4 or More Rings; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Mitochondria; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-raf; Receptor, ErbB-2