Nucleolin-Targeting AS1411 Aptamer-Modified Micelle for the Co-Delivery of Doxorubicin and miR-519c to Improve the Therapeutic Efficacy in Hepatocellular Carcinoma Treatment

Abstract

Background: Multidrug resistance (MDR) has emerged to be a major hindrance in cancer therapy, which contributes to the reduced sensitivity of cancer cells toward chemotherapeutic drugs mainly owing to the over-expression of drug efflux transporters. The combination of gene therapy and chemotherapy has been considered as a potential approach to improve the anti-cancer efficacy by reversing the MDR effect. Materials and Methods: The AS1411 aptamer-functionalized micelles were constructed through an emulsion/solvent evaporation strategy for the simultaneous co-delivery of doxorubicin and miR-519c. The therapeutic efficacy and related mechanism of micelles were explored based on the in vitro and in vivo active targeting ability and the suppression of MDR, using hepatocellular carcinoma cell line HepG2 as a model. Results:The micelle was demonstrated to possess favorable cellular uptake and tumor penetration ability by specifically recognizing the nucleolin in an AS1411 aptamerdependent manner. Further, the intracellular accumulation of doxorubicin was significantly improved due to the suppression of ABCG2-mediated drug efflux by miR-519c, resulting in the efficient inhibition of tumor growth. Conclusion:The micelle-mediated co-delivery of doxorubicin and miR-519c provided a promising strategy to obtain ideal anti-cancer efficacy through the active targeting function and the reversion of MDR.

Oncolytic Impediment/Promotion Balance Disruption by Sonosensitizer-Free Nanoplatforms Unfreezes Autophagy-Induced Resistance to Sonocatalytic Therapy

“…It has been documented that HepG2 cells overexpress nucleolin and AS1411 aptamers can actively recognize and bind with nucleolin . Inspired by this, AS1411-mediated targeted accumulation of the SFTON in HepG2 tumor is expected.…”

“…It has been documented that HepG2 cells overexpress nucleolin 38 and AS1411 aptamers can actively recognize and bind with nucleolin. 39 Inspired by this, AS1411mediated targeted accumulation of the SFTON in HepG2 tumor is expected. Quantitative data derived from inductively coupled plasma atomic emission spectrometry (ICP-AES) also demonstrate it via monitoring the Zn content, where the accumulation of AS1411-chelated PMCS in HepG2 tumors is twofold higher than that of PMCS alone 6 h after injection of the corresponding samples (Figure 6a).…”

“…More significantly, the loaded CQ can further blockade the autophagy process, cut off the self-detoxication of tumor cells, and thus break the oncolytic impediment/promotion balance (Figure ), which is beneficial for abrogating autophagy-induced self-protection effects and unfreezing autophagy-induced resistance to sonocatalytic ROS therapy. Especially after modification with the AS1411 aptamer that can target nucleolin overexpressed specifically in HepG2 tumor cells, , AS1411-mediated active targeting permitted more SFTONs to enter and remain in the liver cancer cells, magnifying the antitumor outcomes. Contributed by the PMCS-enabled persistent ROS production in the SFTON and CQ-unlocked oncolytic impediment/promotion balance disruption, the autophagy-induced self-protection and resistances against tumor therapy were removed, allowing the SFTON to acquire a considerably boosted antitumor efficiency.…”

Broad-Spectrum Theranostics and Biomedical Application of Functionalized Nanomaterials

“…Similarly, Liu et al [ 22 ] reported that the encapsulation of meta -tetra(hydroxyphenyl)chlorine, a photosensitizer, in P23 micelles effectively increased blood circulation kinetics and ultimately enhanced selective photocytotoxicity on A431 cells. As with other studies reporting that multidrug resistance is effectively reversed by combining gene therapy and chemotherapy, Liang et al [ 23 ] reported that the construction of AS1411 aptamer-functionalized micelles by encapsulating doxorubicin and miR-519c enhanced active targeting and suppressedthe multidrug resistance in the hepatocellular carcinoma cell line (HepG2).Apart from cancer, micelles can also be used in the treatment of other diseases such as cardiac toxicity, rheumatoid arthritis, etc. After myocardial infarction, the recruitment of monocytes to the infract through the CCR2 chemokine receptorprolongs inflammation and worsens clinical outcomes.…”

A peptide-DNA hybrid bio-nanomicelle and its application for detection of caspase-3 activity

“…For example, encapsulation of fluorescent 1-pyrenecarboxaldehyde (Py-CHO) molecules into block copolymer-based micelles not only provides a hydrophobic environment for the accommodation of Py-CHO, but also enhances its fluorescence properties ( Gao et al, 2018 ). The excellent stability of micelles and the ideal encapsulation and protection of hydrophobic probes ( Cheng et al, 2021 ; Liang et al, 2021 ) have received much attention in the field of biochemical analysis.…”