An AS1411 aptamer-conjugated liposomal system containing a bubble-generating agent for tumor-specific chemotherapy that overcomes multidrug resistance

摘要

Recent research in chemotherapy has prioritized overcoming the multidrug resistance (MDR) of cancer cells. In this work, liposomes that contain doxorubicin (DOX) and ammonium bicarbonate (ABC, a bubble-generating agent) are prepared and functionalized with an antinucleolin aptamer (AS1411 liposomes) to target DOX-resistant breast cancer cells (MCF-7/ADR), which overexpress nucleolin receptors. Free DOX and liposomes without functionalization with AS1411 (plain liposomes) were used as controls. The results of molecular dynamic simulations suggest that AS1411 functionalization may promote the affinity and specific binding of liposomes to the nucleolin receptors, enhancing their subsequent uptake by tumor cells, whereas plain liposomes enter cells with difficulty. Upon mild heating, the decomposition of ABC that is encapsulated in the liposomes enables the immediate activation of generation of CO2 bubbles, creating permeable defects in their lipid bilayers, and ultimately facilitating the swift intracellular release of DOX. In vivo studies in nude mice that bear tumors demonstrate that the active targeting of AS1411 liposomes can substantially increase the accumulation of DOX in the tumor tissues relative to free DOX or passively targeted plain liposomes, inhibiting tumor growth and reducing systemic side effects, including cardiotoxicity. The above findings indicate that liposomes that are functionalized with AS1411 represent an attractive therapeutic alternative for overcoming the MDR effect, and support a potentially effective strategy for cancer therapy. (C) 2015 Elsevier B.V. All rights reserved.