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

Zi Xian Liao, Er-Tuan Chuang, Chia Chen Lin, Yi Cheng Ho, Kun Ju Lin, Po Yuan Cheng, Ko Jie Chen, Hao Ji Wei, Hsing Wen Sung

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)42-51
Number of pages10
JournalJournal of Controlled Release
Volume208
DOIs
Publication statusPublished - Jun 28 2015
Externally publishedYes

Keywords

  • Cancer therapy
  • Doxorubicin
  • Multidrug resistance
  • Receptor-mediated endocytosis
  • Thermoresponsive liposomes

ASJC Scopus subject areas

  • Pharmaceutical Science

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