Nucleolin-Targeting AS1411-Aptamer-Modified Graft Polymeric Micelle with Dual pH/Redox Sensitivity Designed To Enhance Tumor Therapy through the Codelivery of Doxorubicin/TLR4 siRNA and Suppression of Invasion

In this article, a novel graft polymeric micelle with targeting function ground on aptamer AS1411 was synthesized. The micelle was based on chitosan-ss-polyethylenimine-urocanic acid (CPU) with dual pH/redox sensitivity and targeting effects. This micelle was produced for codelivering Toll-like rece...

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Bibliographic Details
Published in:Molecular pharmaceutics 2018-01, Vol.15 (1), p.314-325
Main Authors: Yang, Shudi, Ren, Zhaoxiang, Chen, Mengtian, Wang, Ying, You, Bengang, Chen, Weiliang, Qu, Chenxi, Liu, Yang, Zhang, Xuenong
Format: Article
Language:English
Subjects:
A549 Cells
Animals
Cell Survival - drug effects
Doxorubicin - administration & dosage
Doxorubicin - chemistry
Doxorubicin - pharmacology
Drug Carriers - chemistry
Drug Liberation
Humans
Mice
Micelles
Nucleolin
Phosphoproteins - chemistry
Phosphoproteins - metabolism
Polymers - chemistry
RNA, Small Interfering
RNA-Binding Proteins - chemistry
RNA-Binding Proteins - metabolism
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Summary:In this article, a novel graft polymeric micelle with targeting function ground on aptamer AS1411 was synthesized. The micelle was based on chitosan-ss-polyethylenimine-urocanic acid (CPU) with dual pH/redox sensitivity and targeting effects. This micelle was produced for codelivering Toll-like receptor 4 siRNA (TLR4–siRNA) and doxorubicin (Dox). In vitro investigation revealed the sustained gene and drug release from Dox–siRNA-loaded micelles under physiological conditions, and this codelivery nanosystem exhibited high dual pH/redox sensitivity, rapid intracellular drug release, and improved cytotoxicity against A549 cells in vitro. Furthermore, the micelles loaded with TLR4–siRNA inhibited the migration and invasion of A549. Excellent tumor penetrating efficacy was also noted in the A549 tumor spheroids and solid tumor slices. In vivo, multiple results demonstrated the excellent tumor-targeting ability of AS1411-chitosan-ss-polyethylenimine-urocanic acid (ACPU) micelle in tumor tissues. The micelles exhibited excellent antitumor efficacy and low toxicity in the systemic circulation in lung-tumor-bearing BALB/c mice. These results conclusively demonstrated the great potential of the new graft copolymer micelle with targeting function for the targeted and efficient codelivery of chemotherapeutic drugs and genes in cancer treatment.
ISSN:1543-8384
1543-8392
DOI:10.1021/acs.molpharmaceut.7b01093