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

Abstract

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.

<p>Aptamer Hybrid Nanocomplexes as Targeting Components for Antibiotic/Gene Delivery Systems and Diagnostics: A Review</p>

“…There is hope to use this novel co-deliver nanosystem in other relevant diseases. [57][58][59][132][133][134] Table 3 describes the types of aptamer-based structures and their roles in gene delivery systems.…”

Chitosan-Based Nanomaterials for Drug Delivery

“…Simultaneously, different types of enzymes and cytokine would increase or decrease in acute and chronic arthritis, and the temperature at the site of inflammation is slightly higher [ 86 ]. Scientists have designed a series of precise environmental (e.g., pH, enzyme, and temperature)-responsive drug delivery vehicles based on the human body [ 87 , 88 ]. The attachment of pH-responsive molecules to CS achieves better responsive characteristics and facilitates drug delivery and release according to the environmental response [ 17 ].…”

“…The SCPs had a significant inhibitory effect especially on DU145 prostate cancer cells and were delivered through the tail vein injection. Zhang et al developed the codelivery of DOX/TLR4 siRNA polymeric micelle with dual pH/redox sensitivity for cancer therapy [ 87 ]. Chitosan and polyethylenimine (PEI) were connected via disulfide bonds, and urocanic acid was decorated on the polymer covalently via amide bonds.…”

Bio‐Conjugated Advanced Materials for Targeted Disease Theranostics

“…For combined chemo‐ and gene therapy, both ssDNA (single‐stranded DNA) and siRNA (small interfering RNA) were crosslinked into nanostructures along with DOX and aptamer CD30 or AS1411 for the targeted therapy in K299 and U937 cells, which highly express CD30, or in HeLa cells . Subsequently, a triangle DNA origami (TO) with MUC1 was loaded by DOX triangle DNA origami, filled with DOX (TOD).…”