Binary-copolymer system base on low-density lipoprotein-coupled N-succinyl chitosan lipoic acid micelles for co-delivery MDR1 siRNA and paclitaxel, enhances antitumor effects via reducing drug.

Abstract

The development of effective and stable carriers of small interfering RNA (siRNA) is important for treating cancer with multidrug resistance (MDR). We developed a new gene and drug co-delivery system and checked its characteristics. Low-density lipoprotein (LDL) was coupled with N-succinyl chitosan (NSC) Lipoic acid (LA) micelles and co-delivered MDR1 siRNA and paclitaxel (PTX-siRNA/LDL-NSC-LA) to enhance antitumor effects by silencing the MDR gene of tumors (Li et al., Adv Mater 2014;26:8217-8224). In our study, we developed a new type of containing paclitaxel-loaded micelles and siRNA-loaded LDL nanoparticle. This "binary polymer" is pH and reduction dual-sensitive core-crosslinked micelles. PTX-siRNA/LDL-NSC-LA had an average particle size of (171.6 ± 6.42) nm, entrapment efficiency of (93.92 ± 1.06) %, and drug-loading amount of (12.35% ± 0.87) %. In vitro, MCF-7 cells, high expressed LDL receptor, were more sensitive to this delivery system than to taxol® and cell activity was inhibited significantly. Fluorescence microscopy showed that PTX-siRNA/LDL-NSC-LA was uptaken very conveniently and played a key role in antitumor activity. PTX-siRNA/LDL-NSC-LA protected the siRNA from degradation by macrophage phagocytosis and evidently down-regulated the level of mdr1 mRNA as well as the expression of P-gp. We tested the target ability of PTX-siRNA/LDL-NSC-LA in vivo in tumor-bearing nude mice. Results showed that this system could directly deliver siRNA and PTX to cancer cells. Thus, new co-delivering siRNA and antitumor drugs should be explored for solving MDR in cancer. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1114-1125, 2017.

• Authors: Shu-Di Yang, Wen-Jing Zhu, Qiao-Ling Zhu, Wei-Liang Chen, Zhao-Xiang Ren, Fang Li, Zhi-Qiang Yuan, Ji-Zhao Li, Yang Liu, Xiao-Feng Zhou, Chun Liu, Xue-Nong Zhang
• Journal: Journal of biomedical materials research. Part B, Applied biomaterials (J Biomed Mater Res B Appl Biomater) Vol. 105 Issue 5 Pg. 1114-1125 (07 2017) ISSN: 1552-4981 [Electronic] United States
• PMID: 27008163 (Publication Type: Journal Article)
• Copyright: © 2016 Wiley Periodicals, Inc.

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Lipoproteins, LDL
• Micelles
• Neoplasm Proteins
• RNA, Small Interfering
• Thioctic Acid
• Chitosan
• Paclitaxel

Topics

• ATP Binding Cassette Transporter, Subfamily B (antagonists & inhibitors, biosynthesis, genetics)
• Animals
• Chitosan (chemistry, pharmacology)
• Female
• Gene Transfer Techniques
• Humans
• Lipoproteins, LDL (chemistry, pharmacology)
• MCF-7 Cells
• Mice
• Mice, Nude
• Micelles
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Neoplasms, Experimental (genetics, metabolism, pathology, therapy)
• Paclitaxel (pharmacology)
• RNA, Small Interfering (biosynthesis, genetics)
• Thioctic Acid (chemistry, pharmacology)
• Xenograft Model Antitumor Assays