A multi-functional PEGylated gold(<scp>iii</scp>) compound: potent anti-cancer properties and self-assembly into nanostructures for drug co-delivery

Abstract

Gold(iii) porphyrin-PEG conjugates [Au(TPP-COO-PEG₅₀₀₀-OCH₃)]Cl (<b>1</b>) and [Au(TPP-CONH-PEG₅₀₀₀-OCH₃)]Cl (<b>2</b>) 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 <b>1</b> in acidic buffer solution as well as <i>in vitro</i> and <i>in vivo</i> without the formation of toxic side products. The nanostructures of <b>1</b> 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 <b>1</b> with excellent selectivity in killing cancer cells compared with non-tumorigenic cells <i>in vitro</i>. This was corroborated by fluorescence microscopy imaging and flow cytometric analysis of co-culture model of colon cancer (HCT116) and normal colon (NCM460) cells. <i>In vivo</i> experiments showed that treatment of nude mice bearing HCT116 xenografts with <b>1</b> 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 <b>1</b> in organs of treated mice at its effective dosage, as compared to that of other gold(iii) porphyrin complexes. Co-assembly of <b>1</b> and doxorubicin resulted in encapsulation of doxorubicin by the nanostructures of <b>1</b>. 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 <b>1</b> not only as an anti-cancer agent but also as a nanoscale drug carrier for chemotherapy.