Targeted Nanoparticles Deliver siRNA to Melanoma

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Targeted Nanoparticles Deliver siRNA to Melanoma Yunching Chen, Surendar R. Bathula, Qi Yang, Leaf Huang Journal of Investigative Dermatology Volume 130, Issue 12, Pages 2790-2798 (December 2010) DOI: 10.1038/jid.2010.222 Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Chemical structures of DSAA and DOTAP. Chemical structures of DSAA (a) and DOTAP (b). DOTAP, 1,2-dioleoyl-3-trimethylammonium-propane; DSAA, N,N-distearyl-N-methyl-N-2-(N′-arginyl) aminoethyl ammonium chloride. Journal of Investigative Dermatology 2010 130, 2790-2798DOI: (10.1038/jid.2010.222) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Intracellular uptake of siRNA and luciferase gene silencing in cultured melanoma cells. (a) Fluorescence micrographs of B16F10 cells after treatment with 5′-Cy-3-labeled siRNA in the targeted nanoparticles (AA+) or the nontargeted nanoparticles (AA-) containing DSAA and DOTAP. Scale bar=50μm. (b) B16F10 cells were incubated with different formulations containing anti-luciferase siRNA. Luciferase activity in cells was measured after 24hours. Each value represents the mean±SD (n=3). DOTAP, 1,2-dioleoyl-3-trimethylammonium-propane; DSAA, N,N-distearyl-N-methyl-N-2-(N′-arginyl) aminoethyl ammonium chloride; Luc, luciferase; siRNA, small interfering RNA. Journal of Investigative Dermatology 2010 130, 2790-2798DOI: (10.1038/jid.2010.222) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Tumor uptake of siRNA and lipid in different formulations. (a) Fluorescence micrographs of Cy-3-siRNA (red) and NBD-cholesterol (green) in B16F10 tumor. Mice were injected with different formulations and killed at 4hours. Scale bar=50μm. (b) Tissue distribution of NBD-cholesterol in mice injected with different formulations. Data=mean±SD, n=3. DSAA: non-PEGylated liposome containing DSAA and cholesterol (1:1mol ratio); siRNA, small interfering RNA. Journal of Investigative Dermatology 2010 130, 2790-2798DOI: (10.1038/jid.2010.222) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 c-Myc expression in the tumor after treatment with siRNA in different formulations. Mice bearing B16F10 tumors were injected intravenously with siRNA formulated in different LPD nanoparticles. c-Myc expression was examined by western blot analysis. LPD, liposome-polycation-DNA; siRNA, small interfering RNA. Journal of Investigative Dermatology 2010 130, 2790-2798DOI: (10.1038/jid.2010.222) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Tumor growth inhibition. (a) B16F10 tumor growth inhibition by siRNA in different formulations. (b) Dose-dependent antitumor activity of c-Myc siRNA formulated in DSAA AA+. (c) The combination of c-Myc siRNA formulated in the targeted DSAA nanoparticles and paclitaxel inhibited B16F10 tumor growth (20mg paclitaxel per kg). Solid arrows indicate the i.v. administrations of siRNA, and dashed-line arrows indicate the i.v. injections of paclitaxel (N=4–7). DSAA, N,N-distearyl-N-methyl-N-2-(N′-arginyl) aminoethyl ammonium chloride; siRNA, small interfering RNA. Journal of Investigative Dermatology 2010 130, 2790-2798DOI: (10.1038/jid.2010.222) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 ROS generation and apoptosis induction by DSAA or DOTAP in mouse melanoma B16F10 cells. (a) Dose-dependent ROS generation by DSAA or DOTAP after 1hour incubation with different concentrations of DSAA or DOTAP. The ROS content of cells was analyzed by flow cytometry. N=3, *P<0.05. (b and c) Dose- and time-dependent apoptosis induction by DSAA or DOTAP in B16F10 cells. (d) Bcl-2 expression in B16F10 cells after incubation with 50μM DSAA and DOTAP for 24 and 48hours. DOTAP, 1,2-dioleoyl-3-trimethylammonium-propane; DSAA, N,N-distearyl-N-methyl-N-2-(N′-arginyl) aminoethyl ammonium chloride; ROS, reactive oxygen species. Journal of Investigative Dermatology 2010 130, 2790-2798DOI: (10.1038/jid.2010.222) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 Apoptosis induction and tumor growth inhibition of human melanoma by nanoparticles containing c-Myc siRNA and DSAA. (a) MDA-MB-435 cells transfected with c-Myc or a control siRNA for 72hours by lipofectamine 2000 and analyzed for Annexin V staining by flow cytometry. (b) Immunofluorescent staining of c-Myc and TUNEL staining in the MDA-MB-435 xenograft tumors after three consecutive i.v. injections of RNAs in targeted nanoparticles DSAA AA+. Scale bar=50μm. (c) Quantitative analysis of TUNEL-positive staining in the tumors treated with different formulations (n=3–6). (d) Comparison of therapeutic efficacy of c-Myc (0.6mgkg−1) and control siRNAs in the targeted nanoparticles DSAA AA+. Arrows indicate the i.v. administrations of siRNA. DSAA, N,N-distearyl-N-methyl-N-2-(N′-arginyl) aminoethyl ammonium chloride; DSASS, N,N-distearyl-N-methyl-N-2-(N′-arginyl) aminoethyl ammonium chloride; SiRNA, small interfering RNA. Journal of Investigative Dermatology 2010 130, 2790-2798DOI: (10.1038/jid.2010.222) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 8 Schematic illustration of possible mechanisms of the combination strategy using c-Myc siRNA and the cationic lipid DSAA. Cyt c, cytochrome c; DSAA, N,N-distearyl-N-methyl-N-2-(N′-arginyl) aminoethyl ammonium chloride; siRNA, small interfering RNA. Journal of Investigative Dermatology 2010 130, 2790-2798DOI: (10.1038/jid.2010.222) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions