pH-triggered degradable polymeric micelles for targeted anti-tumor drug delivery.

Abstract

2-(Octadecyloxy)-1,3-dioxan-5-amine (OD) with an acid degradable ortho ester group was synthesized, and conjugated to hyaluronic acid (HA) backbone to prepare pH-responsive and tumor-targeted hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine (HOD) conjugates. 1H NMR was used to confirm the structures of the OD and HOD. The studies of pH-responsive behavior showed that HOD micelles were stable under physiological conditions while they were degraded in the tumor acidic microenvironment. Doxorubicin (DOX)-loaded HOD micelles (DOX/HOD) with a narrow size distribution were prepared and characterized. The increased release of DOX from DOX/HOD micelles was presented at low pH condition. From in vitro cytotoxicity assays against MCF-7 cells, the blank micelles exhibited low cytotoxicity, but DOX/HOD micelles had the higher cytotoxicity than pH insensitive control and free DOX. Cellular uptake experiments and confocal images demonstrated that pH-sensitive DOX/HOD micelles could be internalized efficiently by CD44 receptor mediated endocytosis, and then DOX was rapidly released due to pH-induced degradable of OD to cell nucleus compared to the non-sensitive micelles. Furthermore, endocytosis inhibition studies presented that DOX/HOD micelles were internalized into cells mainly via caveolae-mediated routes. In vivo study of micelles in tumor-bearing mice indicates that HOD micelles were more effectively accumulated into the tumor tissue than HOA micelles. These results verify that the pH-sensitive HOD micellar system is a promising nanocarrier for enhanced internalization of antitumor drugs to cancer cells.

• Authors: Lipeng Qiu, Mengqin Zhu, Kai Gong, Huanhuan Peng, Lu Ge, Li Zhao, Jinghua Chen
• Journal: Materials science & engineering. C, Materials for biological applications (Mater Sci Eng C Mater Biol Appl) Vol. 78 Pg. 912-922 (Sep 01 2017) ISSN: 1873-0191 [Electronic] Netherlands
• PMID: 28576067 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Micelles
• Doxorubicin

Topics

• Animals
• Antineoplastic Agents (chemistry)
• Cell Line, Tumor
• Doxorubicin
• Drug Delivery Systems
• Humans
• Hydrogen-Ion Concentration
• MCF-7 Cells
• Mice
• Micelles