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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.

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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) Fluorescence microscopy images of co-cultured HCT116 and NCM460 cells stained with FITC-Annexin V and propidium iodide after incubation with 1 (2 μM) for 24 h. The NCM460 cells were pre-treated with blue-emissive CMF2HC dye for differentiation from HCT116 cells. The overlaid image was prepared using ImageJ, with apoptotic cells in green. Analysis by flow cytometry of the co-culture model of NCM460 cells, which were pre-treated by CMF2HC dye, and HCT116 cells after incubation with 1 (2 μM) for 24 h and (b) without and (c) with FITC-Annexin V staining.
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fig4: (a) Fluorescence microscopy images of co-cultured HCT116 and NCM460 cells stained with FITC-Annexin V and propidium iodide after incubation with 1 (2 μM) for 24 h. The NCM460 cells were pre-treated with blue-emissive CMF2HC dye for differentiation from HCT116 cells. The overlaid image was prepared using ImageJ, with apoptotic cells in green. Analysis by flow cytometry of the co-culture model of NCM460 cells, which were pre-treated by CMF2HC dye, and HCT116 cells after incubation with 1 (2 μM) for 24 h and (b) without and (c) with FITC-Annexin V staining.

Mentions: As 1 was found to show faster cellular uptake into HCT116 cells than Au1a (Fig. 3a and c), the induction of apoptosis by 1 after a longer incubation time indicated a time lag for 1 to induce Caspase-3/7 activation in HCT116 cells, when compared to Au1a (Fig. 4a). This can be explained by the time required for 1 to undergo hydrolytic cleavage of the ester bond before exhibiting its anti-cancer properties. Nonetheless, both 1 and Au1a (2 μM) could induce apoptosis in a large population of HCT116 cells after 48 h (Fig. S13b†), suggesting the readiness of hydrolysis of 1 in HCT116 cells and the effective killing of these colon cancer cells by 1. For normal colon NCM460 cells, Au1a (2 μM) induced their apoptosis after incubation for 20 h, which was slightly longer than that found in HCT116 cells, partly owing to its slower uptake into NCM460 cells (Fig. 3a and c). The lack of significant activation of Caspase-3/7 in NCM460 cells after incubation with 1 can be rationalized by the relatively slow uptake of 1 (Fig. 3a and c), in addition to likely slow hydrolytic cleavage of the PEG pendant of 1 in NCM460 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) Fluorescence microscopy images of co-cultured HCT116 and NCM460 cells stained with FITC-Annexin V and propidium iodide after incubation with 1 (2 μM) for 24 h. The NCM460 cells were pre-treated with blue-emissive CMF2HC dye for differentiation from HCT116 cells. The overlaid image was prepared using ImageJ, with apoptotic cells in green. Analysis by flow cytometry of the co-culture model of NCM460 cells, which were pre-treated by CMF2HC dye, and HCT116 cells after incubation with 1 (2 μM) for 24 h and (b) without and (c) with FITC-Annexin V staining.
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fig4: (a) Fluorescence microscopy images of co-cultured HCT116 and NCM460 cells stained with FITC-Annexin V and propidium iodide after incubation with 1 (2 μM) for 24 h. The NCM460 cells were pre-treated with blue-emissive CMF2HC dye for differentiation from HCT116 cells. The overlaid image was prepared using ImageJ, with apoptotic cells in green. Analysis by flow cytometry of the co-culture model of NCM460 cells, which were pre-treated by CMF2HC dye, and HCT116 cells after incubation with 1 (2 μM) for 24 h and (b) without and (c) with FITC-Annexin V staining.
Mentions: As 1 was found to show faster cellular uptake into HCT116 cells than Au1a (Fig. 3a and c), the induction of apoptosis by 1 after a longer incubation time indicated a time lag for 1 to induce Caspase-3/7 activation in HCT116 cells, when compared to Au1a (Fig. 4a). This can be explained by the time required for 1 to undergo hydrolytic cleavage of the ester bond before exhibiting its anti-cancer properties. Nonetheless, both 1 and Au1a (2 μM) could induce apoptosis in a large population of HCT116 cells after 48 h (Fig. S13b†), suggesting the readiness of hydrolysis of 1 in HCT116 cells and the effective killing of these colon cancer cells by 1. For normal colon NCM460 cells, Au1a (2 μM) induced their apoptosis after incubation for 20 h, which was slightly longer than that found in HCT116 cells, partly owing to its slower uptake into NCM460 cells (Fig. 3a and c). The lack of significant activation of Caspase-3/7 in NCM460 cells after incubation with 1 can be rationalized by the relatively slow uptake of 1 (Fig. 3a and c), in addition to likely slow hydrolytic cleavage of the PEG pendant of 1 in NCM460 cells.

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.

No MeSH data available.