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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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Evaluation of systemic toxicity in nude mice bearing HCT116 xenografts after treatment with 1 or 3. (a) H & E staining of lung, liver, kidney, heart and spleen sections from HCT116 xenografted nude mice (n = 8) at 24 days post-treatment. The black arrows in lung, liver and kidney sections denote sites of pulmonary hemorrhage, apoptotic cells and swollen epithelial cells, respectively. Blood biochemistry analysis of (b) ALT, (c) AST, (d) GLB, (e) BUN, (f) CREA, (g) UA, (h) LDH and (i) CK in the mice (n = 8) at 24 days post-treatment. Bars with different characters were statistically significant at p < 0.05 level.
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fig7: Evaluation of systemic toxicity in nude mice bearing HCT116 xenografts after treatment with 1 or 3. (a) H & E staining of lung, liver, kidney, heart and spleen sections from HCT116 xenografted nude mice (n = 8) at 24 days post-treatment. The black arrows in lung, liver and kidney sections denote sites of pulmonary hemorrhage, apoptotic cells and swollen epithelial cells, respectively. Blood biochemistry analysis of (b) ALT, (c) AST, (d) GLB, (e) BUN, (f) CREA, (g) UA, (h) LDH and (i) CK in the mice (n = 8) at 24 days post-treatment. Bars with different characters were statistically significant at p < 0.05 level.

Mentions: The anti-tumor experiments using mice were approved by the animal ethics committees of Jinan University and The University of Hong Kong. Treatment of nude mice bearing HCT116 xenografts with 1 (2 or 4 mg kg–1) for 24 days through intravenous injection resulted in a significant reduction of tumor weight (35 and 53%, respectively; p < 0.01, n = 8; Fig. 6b) and tumor volume (41 and 58% respectively; p < 0.01, n = 8; Fig. 6c), with no mouse death or significant loss in body weight (Fig. 6d). Histopathological analysis of the tissues of treated mice revealed that no significant anomaly was observed in lung, liver, kidney, heart and spleen after treatment with 1 (Fig. 7a). The low systemic toxicity of 1 was further supported by the blood biochemistry of nude mice after treatment with 1 (4 mg kg–1; Fig. 7b–i); plasma levels of several organ damage indicators including alanine transaminase (ALT), globulin (GLB), blood urea nitrogen (BUN) and creatine kinase (CK) of the treated mice were lower than those of the untreated mice bearing HCT116 xenografts (p < 0.05; Fig. 7b, d, e and g), and fell within the statistically relevant range of those of mice without the xenograft. In addition, [Au(TPP–COOH)]+ was found in the UPLC-QTOF-MS of tumor tissues of mice treated by 1, supporting the propensity for hydrolysis of 1in vivo (Fig. S22†).


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.
Evaluation of systemic toxicity in nude mice bearing HCT116 xenografts after treatment with 1 or 3. (a) H & E staining of lung, liver, kidney, heart and spleen sections from HCT116 xenografted nude mice (n = 8) at 24 days post-treatment. The black arrows in lung, liver and kidney sections denote sites of pulmonary hemorrhage, apoptotic cells and swollen epithelial cells, respectively. Blood biochemistry analysis of (b) ALT, (c) AST, (d) GLB, (e) BUN, (f) CREA, (g) UA, (h) LDH and (i) CK in the mice (n = 8) at 24 days post-treatment. Bars with different characters were statistically significant at p < 0.05 level.
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Related In: Results  -  Collection

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fig7: Evaluation of systemic toxicity in nude mice bearing HCT116 xenografts after treatment with 1 or 3. (a) H & E staining of lung, liver, kidney, heart and spleen sections from HCT116 xenografted nude mice (n = 8) at 24 days post-treatment. The black arrows in lung, liver and kidney sections denote sites of pulmonary hemorrhage, apoptotic cells and swollen epithelial cells, respectively. Blood biochemistry analysis of (b) ALT, (c) AST, (d) GLB, (e) BUN, (f) CREA, (g) UA, (h) LDH and (i) CK in the mice (n = 8) at 24 days post-treatment. Bars with different characters were statistically significant at p < 0.05 level.
Mentions: The anti-tumor experiments using mice were approved by the animal ethics committees of Jinan University and The University of Hong Kong. Treatment of nude mice bearing HCT116 xenografts with 1 (2 or 4 mg kg–1) for 24 days through intravenous injection resulted in a significant reduction of tumor weight (35 and 53%, respectively; p < 0.01, n = 8; Fig. 6b) and tumor volume (41 and 58% respectively; p < 0.01, n = 8; Fig. 6c), with no mouse death or significant loss in body weight (Fig. 6d). Histopathological analysis of the tissues of treated mice revealed that no significant anomaly was observed in lung, liver, kidney, heart and spleen after treatment with 1 (Fig. 7a). The low systemic toxicity of 1 was further supported by the blood biochemistry of nude mice after treatment with 1 (4 mg kg–1; Fig. 7b–i); plasma levels of several organ damage indicators including alanine transaminase (ALT), globulin (GLB), blood urea nitrogen (BUN) and creatine kinase (CK) of the treated mice were lower than those of the untreated mice bearing HCT116 xenografts (p < 0.05; Fig. 7b, d, e and g), and fell within the statistically relevant range of those of mice without the xenograft. In addition, [Au(TPP–COOH)]+ was found in the UPLC-QTOF-MS of tumor tissues of mice treated by 1, supporting the propensity for hydrolysis of 1in vivo (Fig. S22†).

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