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A multi-functional PEGylated gold( iii ) compound: potent anti-cancer properties and self-assembly into nanostructures for drug co-delivery † † Electronic supplementary information (ESI) available: Experimental details, 1 H NMR and MALDI-TOF-MS of 1 and 2 ; TEM image, DLS profile and zeta potential profile of 2 ; zeta potential profiles of 1 and NC1 ; cell viability profiles after treatment of the gold( iii ) complexes and nanocomposites; total-ion chromatograms of UPLC-QTOF-MS of 1 , 3 and 4 ; cellular uptake of the gold( iii ) complexes; fluorescence microscopy images and flow cytometric analysis of the assay with FITC-Annexin V and propidium iodide; time-dependent fluorescence microscopy images and flow cytometric analysis of the assay using CellEvent ™ Caspase-3/7 Green ReadyProbes Reagent; fluorescence microscopy images and flow cytometric analysis of the co-culture model of HCT116 and NCM460 cells; selected-ion chromatograms from UPLC-QTOF-MS of homogenized tumor tissues of mice treated by 1 ; biodistribution of gold complexes in nude mice bearing HCT116 xenografts; UPLC traces of the nanocomposites; tables showing the relative toxicities of the gold( iii ) complexes and nanocomposites toward cancer cells over non-tumorigenic cells. See DOI: 10.1039/c6sc03210a Click here for additional data file.

View Article: PubMed Central - PubMed

ABSTRACT

1211111111: Gold(iii) porphyrin–PEG conjugates [Au(TPP–COO–PEG5000–OCH3)]Cl () and [Au(TPP–CONH–PEG5000–OCH3)]Cl () have been synthesized and characterized. Based on the amphiphilic character of the conjugates, they were found to undergo self-assembly into nanostructures with size 120–200 nm and this did not require the presence of other surfactants or components for nano-assembly, unlike most conventional drug nano-formulations. With a readily hydrolyzable ester linkage, chemotherapeutic [Au(TPP–COOH)]+ exhibited triggered release from the conjugate in acidic buffer solution as well as in vitro and in vivo without the formation of toxic side products. The nanostructures of showed higher cellular uptake into cancer cells compared to non-tumorigenic cells, owing to their energy-dependent uptake mechanism. This, together with a generally higher metabolic rate and more acidic nature of cancer cells which can lead to faster hydrolysis of the ester bond, afforded with excellent selectivity in killing cancer cells compared with non-tumorigenic cells in vitro. This was corroborated by fluorescence microscopy imaging and flow cytometric analysis of co-culture model of colon cancer (HCT116) and normal colon (NCM460) cells. In vivo experiments showed that treatment of nude mice bearing HCT116 xenografts with resulted in significant inhibition of tumor growth and, more importantly, minimal systemic toxicity as revealed by histopathological analysis of tissue sections and blood biochemisty. The latter is explained by a lower accumulation of in organs of treated mice at its effective dosage, as compared to that of other gold(iii) porphyrin complexes. Co-assembly of and doxorubicin resulted in encapsulation of doxorubicin by the nanostructures of . The nanocomposites demonstrated a strong synergism on killing cancer cells and could overcome efflux pump-mediated drug-resistance in a doxorubicin-resistant ovarian cancer cell line (A2780adr) which was found in cells incubated with doxorubicin alone. Also, the nanocomposites accumulated more slowly in non-tumorigenic cells, resulting in a lower toxicity toward non-tumorigenic cells. These results indicate the potential application of not only as an anti-cancer agent but also as a nanoscale drug carrier for chemotherapy.

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(a) Uptake of 1, 3 or Au1a (all at 2 μM), in terms of the gold content determined by ICP-MS, into HCT116 and NCM460 cells, respectively, after incubation at 37 °C for the indicated time intervals. (b) Uptake of (black) 1, (red) 3, (blue) Au1a or (dark cyan) nanocomposites of 1 and DOX, NC1, ([1] = 2 μM) into (solid line) A2780 and (dashed line) A2780adr cells, respectively, after incubation at 37 °C for the indicated time intervals. (c) Bar chart showing the ratio of uptake of the complexes (2 μM) into cancer and non-tumorigenic cells after incubation for 2 h at 37 °C. (d) Uptake of 1 into HCT116 and NCM460 cells after incubation for 2 h in (black) cell culture medium with 10 vol% fetal bovine serum at 37 °C, (red) cell culture medium with 10 vol% fetal bovine serum and 0.45 M sucrose at 37 °C, (blue) aqueous buffer solution (140 mM NaCl, 20 mM HEPES, 1 mM CaCl2, 1 mM MgCl2 and 1 g L–1d-glucose, pH 7.4) at 37 °C and (green) cell culture medium with 10 vol% fetal bovine serum at 4 °C. All the data are shown as mean ± SEM from three independent experiments. ** denotes p < 0.01 vs. experiment with cell culture medium.
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fig3: (a) Uptake of 1, 3 or Au1a (all at 2 μM), in terms of the gold content determined by ICP-MS, into HCT116 and NCM460 cells, respectively, after incubation at 37 °C for the indicated time intervals. (b) Uptake of (black) 1, (red) 3, (blue) Au1a or (dark cyan) nanocomposites of 1 and DOX, NC1, ([1] = 2 μM) into (solid line) A2780 and (dashed line) A2780adr cells, respectively, after incubation at 37 °C for the indicated time intervals. (c) Bar chart showing the ratio of uptake of the complexes (2 μM) into cancer and non-tumorigenic cells after incubation for 2 h at 37 °C. (d) Uptake of 1 into HCT116 and NCM460 cells after incubation for 2 h in (black) cell culture medium with 10 vol% fetal bovine serum at 37 °C, (red) cell culture medium with 10 vol% fetal bovine serum and 0.45 M sucrose at 37 °C, (blue) aqueous buffer solution (140 mM NaCl, 20 mM HEPES, 1 mM CaCl2, 1 mM MgCl2 and 1 g L–1d-glucose, pH 7.4) at 37 °C and (green) cell culture medium with 10 vol% fetal bovine serum at 4 °C. All the data are shown as mean ± SEM from three independent experiments. ** denotes p < 0.01 vs. experiment with cell culture medium.

Mentions: The uptake of 1 and 3, and Au1a by cancer cells and non-tumorigenic cells was examined in terms of the gold content in the cell lysates using ICP-MS. In contrast to the gold(iii) complexes without PEG conjugation, i.e.3 and Au1a, the gold(iii) porphyrin–PEG conjugate 1 was found to show faster cellular uptake into a variety of cancer cells, such as colorectal carcinoma (HCT116), human ovarian carcinoma (A2780), and its drug-resistant variant (A2780adr; Fig. 3a–c). Interestingly, the uptake of 1 into non-tumorigenic colon and liver cells (NCM460 and MIHA respectively) was found to be lower than that of 3 and Au1a (Fig. 3a and S10†), resulting in significantly higher uptake into cancer cells compared to that into non-tumorigenic cells (Fig. 3c). On the other hand, the uptake of 1 into cancer cells was inhibited by lowered temperature, depletion of K+ concentration and hypertonic sucrose concentration, unlike the uptake of 3 which was not significantly affected by these parameters (Fig. 3d, S11 and S12†). This suggests that the nanostructures of 1 likely entered live cells by energy-dependent clathrin-mediated endocytosis, which is in accordance with reported mechanisms of cellular uptake of nanostructures.30,32 Due to the generally higher metabolic rate of cancer cells than normal cells, 1 showed faster accumulation in cancer cells compared with non-tumorigenic cells (Fig. 3a–c). It is worth noting that 1 exhibited an increasing concentration in both A2780 and A2780adr cells with time, while 3 and Au1a revealed decreases in the amount in A2780adr cells after incubation for 0.75 and 0.5 h, respectively (Fig. 3b). The decrease of 3 and Au1a in A2780adr cells were likely due to the P-glycoprotein-mediated drug-resistance of A2780adr cells,53 while the accumulation of 1 in A2780adr cells suggested that the nanostructures of 1 could overcome the efflux pump-mediated drug-resistance in these cells.


A multi-functional PEGylated gold( iii ) compound: potent anti-cancer properties and self-assembly into nanostructures for drug co-delivery † † Electronic supplementary information (ESI) available: Experimental details, 1 H NMR and MALDI-TOF-MS of 1 and 2 ; TEM image, DLS profile and zeta potential profile of 2 ; zeta potential profiles of 1 and NC1 ; cell viability profiles after treatment of the gold( iii ) complexes and nanocomposites; total-ion chromatograms of UPLC-QTOF-MS of 1 , 3 and 4 ; cellular uptake of the gold( iii ) complexes; fluorescence microscopy images and flow cytometric analysis of the assay with FITC-Annexin V and propidium iodide; time-dependent fluorescence microscopy images and flow cytometric analysis of the assay using CellEvent ™ Caspase-3/7 Green ReadyProbes Reagent; fluorescence microscopy images and flow cytometric analysis of the co-culture model of HCT116 and NCM460 cells; selected-ion chromatograms from UPLC-QTOF-MS of homogenized tumor tissues of mice treated by 1 ; biodistribution of gold complexes in nude mice bearing HCT116 xenografts; UPLC traces of the nanocomposites; tables showing the relative toxicities of the gold( iii ) complexes and nanocomposites toward cancer cells over non-tumorigenic cells. See DOI: 10.1039/c6sc03210a Click here for additional data file.
(a) Uptake of 1, 3 or Au1a (all at 2 μM), in terms of the gold content determined by ICP-MS, into HCT116 and NCM460 cells, respectively, after incubation at 37 °C for the indicated time intervals. (b) Uptake of (black) 1, (red) 3, (blue) Au1a or (dark cyan) nanocomposites of 1 and DOX, NC1, ([1] = 2 μM) into (solid line) A2780 and (dashed line) A2780adr cells, respectively, after incubation at 37 °C for the indicated time intervals. (c) Bar chart showing the ratio of uptake of the complexes (2 μM) into cancer and non-tumorigenic cells after incubation for 2 h at 37 °C. (d) Uptake of 1 into HCT116 and NCM460 cells after incubation for 2 h in (black) cell culture medium with 10 vol% fetal bovine serum at 37 °C, (red) cell culture medium with 10 vol% fetal bovine serum and 0.45 M sucrose at 37 °C, (blue) aqueous buffer solution (140 mM NaCl, 20 mM HEPES, 1 mM CaCl2, 1 mM MgCl2 and 1 g L–1d-glucose, pH 7.4) at 37 °C and (green) cell culture medium with 10 vol% fetal bovine serum at 4 °C. All the data are shown as mean ± SEM from three independent experiments. ** denotes p < 0.01 vs. experiment with cell culture medium.
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fig3: (a) Uptake of 1, 3 or Au1a (all at 2 μM), in terms of the gold content determined by ICP-MS, into HCT116 and NCM460 cells, respectively, after incubation at 37 °C for the indicated time intervals. (b) Uptake of (black) 1, (red) 3, (blue) Au1a or (dark cyan) nanocomposites of 1 and DOX, NC1, ([1] = 2 μM) into (solid line) A2780 and (dashed line) A2780adr cells, respectively, after incubation at 37 °C for the indicated time intervals. (c) Bar chart showing the ratio of uptake of the complexes (2 μM) into cancer and non-tumorigenic cells after incubation for 2 h at 37 °C. (d) Uptake of 1 into HCT116 and NCM460 cells after incubation for 2 h in (black) cell culture medium with 10 vol% fetal bovine serum at 37 °C, (red) cell culture medium with 10 vol% fetal bovine serum and 0.45 M sucrose at 37 °C, (blue) aqueous buffer solution (140 mM NaCl, 20 mM HEPES, 1 mM CaCl2, 1 mM MgCl2 and 1 g L–1d-glucose, pH 7.4) at 37 °C and (green) cell culture medium with 10 vol% fetal bovine serum at 4 °C. All the data are shown as mean ± SEM from three independent experiments. ** denotes p < 0.01 vs. experiment with cell culture medium.
Mentions: The uptake of 1 and 3, and Au1a by cancer cells and non-tumorigenic cells was examined in terms of the gold content in the cell lysates using ICP-MS. In contrast to the gold(iii) complexes without PEG conjugation, i.e.3 and Au1a, the gold(iii) porphyrin–PEG conjugate 1 was found to show faster cellular uptake into a variety of cancer cells, such as colorectal carcinoma (HCT116), human ovarian carcinoma (A2780), and its drug-resistant variant (A2780adr; Fig. 3a–c). Interestingly, the uptake of 1 into non-tumorigenic colon and liver cells (NCM460 and MIHA respectively) was found to be lower than that of 3 and Au1a (Fig. 3a and S10†), resulting in significantly higher uptake into cancer cells compared to that into non-tumorigenic cells (Fig. 3c). On the other hand, the uptake of 1 into cancer cells was inhibited by lowered temperature, depletion of K+ concentration and hypertonic sucrose concentration, unlike the uptake of 3 which was not significantly affected by these parameters (Fig. 3d, S11 and S12†). This suggests that the nanostructures of 1 likely entered live cells by energy-dependent clathrin-mediated endocytosis, which is in accordance with reported mechanisms of cellular uptake of nanostructures.30,32 Due to the generally higher metabolic rate of cancer cells than normal cells, 1 showed faster accumulation in cancer cells compared with non-tumorigenic cells (Fig. 3a–c). It is worth noting that 1 exhibited an increasing concentration in both A2780 and A2780adr cells with time, while 3 and Au1a revealed decreases in the amount in A2780adr cells after incubation for 0.75 and 0.5 h, respectively (Fig. 3b). The decrease of 3 and Au1a in A2780adr cells were likely due to the P-glycoprotein-mediated drug-resistance of A2780adr cells,53 while the accumulation of 1 in A2780adr cells suggested that the nanostructures of 1 could overcome the efflux pump-mediated drug-resistance in these cells.

View Article: PubMed Central - PubMed

ABSTRACT

1211111111: Gold(iii) porphyrin&ndash;PEG conjugates [Au(TPP&ndash;COO&ndash;PEG5000&ndash;OCH3)]Cl () and [Au(TPP&ndash;CONH&ndash;PEG5000&ndash;OCH3)]Cl () have been synthesized and characterized. Based on the amphiphilic character of the conjugates, they were found to undergo self-assembly into nanostructures with size 120&ndash;200 nm and this did not require the presence of other surfactants or components for nano-assembly, unlike most conventional drug nano-formulations. With a readily hydrolyzable ester linkage, chemotherapeutic [Au(TPP&ndash;COOH)]+ exhibited triggered release from the conjugate in acidic buffer solution as well as in vitro and in vivo without the formation of toxic side products. The nanostructures of showed higher cellular uptake into cancer cells compared to non-tumorigenic cells, owing to their energy-dependent uptake mechanism. This, together with a generally higher metabolic rate and more acidic nature of cancer cells which can lead to faster hydrolysis of the ester bond, afforded with excellent selectivity in killing cancer cells compared with non-tumorigenic cells in vitro. This was corroborated by fluorescence microscopy imaging and flow cytometric analysis of co-culture model of colon cancer (HCT116) and normal colon (NCM460) cells. In vivo experiments showed that treatment of nude mice bearing HCT116 xenografts with resulted in significant inhibition of tumor growth and, more importantly, minimal systemic toxicity as revealed by histopathological analysis of tissue sections and blood biochemisty. The latter is explained by a lower accumulation of in organs of treated mice at its effective dosage, as compared to that of other gold(iii) porphyrin complexes. Co-assembly of and doxorubicin resulted in encapsulation of doxorubicin by the nanostructures of . The nanocomposites demonstrated a strong synergism on killing cancer cells and could overcome efflux pump-mediated drug-resistance in a doxorubicin-resistant ovarian cancer cell line (A2780adr) which was found in cells incubated with doxorubicin alone. Also, the nanocomposites accumulated more slowly in non-tumorigenic cells, resulting in a lower toxicity toward non-tumorigenic cells. These results indicate the potential application of not only as an anti-cancer agent but also as a nanoscale drug carrier for chemotherapy.

No MeSH data available.


Related in: MedlinePlus