Multi‐Catcher Polymers Regulate the Nucleolin Cluster on the Cell Surface for Cancer Therapy

Abstract

Cell signal transduction mediated by cell surface ligand‐receptor is crucial for regulating cell behavior. The oligomerization or hetero‐aggregation of the membrane receptor driven by the ligand realizes the rearrangement of apoptotic signals, providing a new ideal tool for tumor therapy. However, the construction of a stable model of cytomembrane receptor aggregation and the development of a universal anti‐tumor therapy model on the cellular surface remain challenging. This work describes the construction of a “multi‐catcher” flexible structure GC‐chol‐apt‐cDNA with a suitable integration of the oligonucleotide aptamer (apt) and cholesterol (chol) on a polymer skeleton glycol chitosan (GC), for the regulation of the nucleolin cluster through strong polyvalent binding and hydrophobic membrane anchoring on the cell surface. This oligonucleotide aptamer shows nearly 100‐fold higher affinity than that of the monovalent aptamer and achieves stable anchoring to the plasma membrane for up to 6 h. Moreover, it exerts a high tumor inhibition both in vitro and in vivo by activating endogenous mitochondrial apoptosis pathway through the cluster of nucleolins on the cell membrane. This multi‐catcher nano‐platform combines the spatial location regulation of cytomembrane receptors with the intracellular apoptotic signaling cascade and represents a promising strategy for antitumor therapy.

Multivalent dendritic DNA aptamer molecules for the enhancement of therapeutic effects

“…However, when the valency increased from three to six and nine, the increase in the aptamer's valency on DNA dendrons did not induce a significant increase in antiproliferative activity. We consider that this result could be due to the following reason: 3-Branched AS1411 could interact with multiple nucleolin molecules leading to a stronger antiproliferative effect than the same amount of the monovalent aptamer, 30 however, this interaction could be hindered by the steric hindrance resulting from a higher density of aptamer moieties, as previously reported in DNA dendrons incorporating TLR9 ligands. 14 Further studies are underway to improve the antiproliferative activity considering the steric hindrance derived from the higher density of aptamer moieties in 6-Branched AS1411 and 9-Branched AS1411.…”

DNA-Based Fluorescent Nanoprobe for Cancer Cell Membrane Imaging

“…Receptors are a class of protein molecules that serve as subcellular cell surfaces or intracellular components. Receptors on the cell membrane play important roles in a variety of physiological and pathological processes and have become therapeutic targets for a large number of drugs [ 57 , 58 ]. G-protein-coupled receptors (GPCRs) and enzyme-linked receptors (especially RTKs) are the two largest known receptors among the thousands of known cell surface receptors in eukaryotes, and they also represent one of the hottest topics in the field of life science [ 59 ].…”

“…Recognizing extracellular stimuli and transducing cell signal pathways, cell surface receptors regulate fundamental cell behaviors, such as proliferation, migration, and differentiation [ 60 ]. Numerous membrane receptors, such as MUC1 [ 61 ], nucleolin [ 57 ], EGFR [ 62 ], epithelial cell adhesion molecules [ 63 ], etc., have been considered tumor markers and used for the specific imaging of cancer cells up to this point. The majority of these receptors are RTKs and participate in numerous intracellular signaling pathways associated with the growth and proliferation of cancer cells [ 64 ].…”

Engineered aptamers for molecular imaging

“…Moreover, nanomaterials serve as carriers for delivering aptamers and function as signal molecules in various imaging modalities. Currently, there are numerous applications of aptamer–nanomaterial conjugates in molecular imaging, including microspheres, 115,116 nanoparticles (NPs), 117 lipid nanoparticle formulations (LNPs), 118,119 polymers, 120–122 MOF 123 and other nanomaterials. 124…”