A54 Peptide Modified and Redox-Responsive Glucolipid Conjugate Micelles for Intracellular Delivery of Doxorubicin in Hepatocarcinoma Therapy.

Redox-responsive nanomaterials applied in drug delivery systems (DDS) have attracted an increasing attention in pharmaceutical research as a carrier for antitumor therapy. However, there would be unwanted drug release from a redox-responsive DDS with no selection at nontarget sites, leading to undesirable toxicities in normal tissues and cells. Here, an A54 peptide modified and PEGylated reduction cleavable glucolipid conjugate (A54-PEG-CSO-ss-SA, abbreviated to APCss A) was designed for intracellular delivery of doxorubicin (DOX). The synthesized APCss A could be assembled via micellization self-assembly in aqueous water above the critical micelle concentration (54.9 μg/mL) and exhibited a high drug encapsulation efficiency (77.92%). The APCss A micelles showed an enhanced redox sensitivity in that the disulfide bond could be degraded quickly and the drug would be released from micelles in 10 mM levels of glutathione (GSH). The cellular uptake studies highlighted the affinity of APCss A micelles toward the hepatoma cells (BEL-7402) compared to that toward HepG2 cells. In contrast with the nonresponsive conjugate, the drug was released from APCss A micelles more quickly in 10 mM level of GSH concentration (tumor cells). Moreover, the DOX-loaded APCss A micelles displayed an increased cytotoxicity which was 1.6- to 2.0-fold that of unmodified and nonresponsive micelles. In vivo, the APCss A micelles had stronger distribution to liver and hepatoma tissue and prolonged the circulation and retention time, while the drug release only occurred in the tumor tissue. The APCss A/DOX showed the tumor inhibition rate equal to that of commercial doxorubicin hydrochloric without negative consequence. This study suggested that the APCss A/DOX showed promising potential to treat the tumor for its special tumor targeting, selective intracellular drug release, enhanced antitumor activity, and reduced toxicity on normal tissues.