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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) Chemical structures of 1–4 and Au1a. (b) Multi-functional properties of 1. (c) Schematic cartoon showing the preparations of nanostructures of 1 and nanocomposites of 1 and DOX by the self-assembly of 1.
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sch1: (a) Chemical structures of 1–4 and Au1a. (b) Multi-functional properties of 1. (c) Schematic cartoon showing the preparations of nanostructures of 1 and nanocomposites of 1 and DOX by the self-assembly of 1.

Mentions: The chemical structures of complexes 1–4 and Au1a are depicted in Scheme 1. The gold(iii) porphyrin–PEG conjugates are decorated with multiple functionalities for their anti-cancer properties. The PEG pendant can render gold(iii) porphyrin complexes with good aqueous solubility while lessening the reactivity of the complex with biomolecules. Importantly, PEG also provides complexes with amphiphilic character so that the gold(iii) porphyrin–PEG conjugates can undergo self-assembly into nanostructures in aqueous media. These properties are important for improving the in vivo efficacy of gold(iii) porphyrin complexes for anti-cancer treatment with reduced toxic side effects. To avoid significantly lowering the cytotoxicity of the gold(iii) porphyrin complexes by the PEG pendant as observed in other PEG–drug conjugates,47 the ester linkage, which can be hydrolyzed readily by intracellular esterases and/or acidic conditions in the tumor vicinity,34,49 was employed to conjugate the PEG and gold(iii) porphyrin moiety (complex 1). The amide counterpart, 2, was also synthesized and examined to understand the contribution of the cleavable ester linkage on the anti-cancer properties of gold(iii) porphyrin–PEG conjugates. It is noteworthy that hydrolysis of the conjugates would only release the anti-cancer gold(iii) porphyrin moiety and the hydrolyzed product of FDA approved PEG. Therefore, no additional toxicity would result from the conjugates compared to the gold(iii) porphyrin complex alone.


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) Chemical structures of 1–4 and Au1a. (b) Multi-functional properties of 1. (c) Schematic cartoon showing the preparations of nanostructures of 1 and nanocomposites of 1 and DOX by the self-assembly of 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5384453&req=5

sch1: (a) Chemical structures of 1–4 and Au1a. (b) Multi-functional properties of 1. (c) Schematic cartoon showing the preparations of nanostructures of 1 and nanocomposites of 1 and DOX by the self-assembly of 1.
Mentions: The chemical structures of complexes 1–4 and Au1a are depicted in Scheme 1. The gold(iii) porphyrin–PEG conjugates are decorated with multiple functionalities for their anti-cancer properties. The PEG pendant can render gold(iii) porphyrin complexes with good aqueous solubility while lessening the reactivity of the complex with biomolecules. Importantly, PEG also provides complexes with amphiphilic character so that the gold(iii) porphyrin–PEG conjugates can undergo self-assembly into nanostructures in aqueous media. These properties are important for improving the in vivo efficacy of gold(iii) porphyrin complexes for anti-cancer treatment with reduced toxic side effects. To avoid significantly lowering the cytotoxicity of the gold(iii) porphyrin complexes by the PEG pendant as observed in other PEG–drug conjugates,47 the ester linkage, which can be hydrolyzed readily by intracellular esterases and/or acidic conditions in the tumor vicinity,34,49 was employed to conjugate the PEG and gold(iii) porphyrin moiety (complex 1). The amide counterpart, 2, was also synthesized and examined to understand the contribution of the cleavable ester linkage on the anti-cancer properties of gold(iii) porphyrin–PEG conjugates. It is noteworthy that hydrolysis of the conjugates would only release the anti-cancer gold(iii) porphyrin moiety and the hydrolyzed product of FDA approved PEG. Therefore, no additional toxicity would result from the conjugates compared to the gold(iii) porphyrin complex alone.

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.