Terminal Structure of Triethylene Glycol-Tethered Chains on β-Cyclodextrin-Threaded Polyrotaxanes Dominates Temperature Responsivity and Biointeractions

Abstract

Pharmacological and biomedical applications of cyclodextrin (CD)-threaded polyrotaxanes (PRXs) have gained increasing attention. We had previously investigated the therapeutic effects of oligo(ethylene glycol) (OEG)-modified β-CD PRXs in congenital metabolic disorders. Although the chemical modification of PRXs is crucial for these applications, the influences of the chemical structure of OEG modified on PRXs were not completely understood. The current study focuses on the terminal group structures of triethylene glycol (TEG)-tethered chains, wherein three series of TEG-tethered PRXs (TEG−PRXs) with various TEG terminal group structures (hydroxy, methoxy, and ethoxy) were synthesized to investigate their physicochemical properties and biointeractions. The methoxy and ethoxy-terminated TEG−PRXs exhibited temperature-dependent phase transitions in phosphate buffer saline and formed coacervate droplets above their cloud points. A comprehensive analysis revealed that the hydrophobicity of the terminal group structures of the TEG-tethered chains played a dominant role in exhibiting temperature-dependent phase transition. Furthermore, the hydrophobicity of the terminal group structures of TEG-tethered chains on PRXs also affected the interactions with lipids and proteins, with the hydrophobic ethoxy-terminated TEG-tethered chains showing the highest interactions. However, in normal human skin fibroblasts, the moderately hydrophobic methoxy-terminated TEG-modified PRXs showed the highest intracellular uptake levels. As a result, we concluded that methoxy-terminated TEG is a suitable chemical modification for the biomedical applications of PRXs due to the negligible temperature responsivity around physiological temperature and significant intracellular uptake levels. The findings of this study shall contribute significantly to the rational design of PRXs and CD-based materials for future pharmacological and biomedical applications.

Cografting of Zwitterionic Sulfobetaines and Cationic Amines on β-Cyclodextrin-Threaded Polyrotaxanes Facilitates Cellular Association and Tissue Accumulation with High Biocompatibility

“…Chemical modification of threaded β-CDs is necessary for the molecular design of PRXs for pharmacological applications because unmodified PRXs are insoluble in aqueous solutions. We have developed various water-soluble β-CD PRXs by chemical modification with hydrophilic functional groups such as short oligo­(ethylene glycol) chains, methyl groups, and carboxy groups. ,− In addition, we examined the structure–function relationships of these chemically modified β-CD PRXs, and some functional groups contributed to improve not only aqueous solubility but also functionalities, such as stimuli-responsivity, self-assembly, and cellular association behaviors. − However, the improvement of β-CD PRX functionalities, especially cellular association, biodistribution, and biocompatibility, remains a challenging issue for their pharmacological applications.…”

Exploring Receptor Binding Affinities and Hepatic Cell Association of N-Acetyl-d-Galactosamine-Modified β-Cyclodextrin-Based Polyrotaxanes for Liver-Targeted Therapies

“…In our previous study, the hydrophobicity of the terminal chemical structure of the oligo­(ethylene glycol) tethered chains of PRX was attributed to the temperature-dependent phase transition in aqueous solutions . To verify the effects of terminal azide groups and GalNAc in AE 4 -PRXs and GalNAc-PRXs, the temperature dependence of the transmittance was measured in PBS.…”

“…Cy5.5-labeled 59GalNAc-PRX, 77GalNAc-PRX, 75Man-PRX, and 68GalNAc-amylose were synthesized and characterized in the same manner. Cy5.5-labeled 78HEE-PRX was synthesized and characterized according to a previously reported method …”

Thermoresponsive Microgels from Cyclodextrin-Based Polyrotaxanes with Photomodulated Degradation

“…Oligoethylene glycol (OEG)-modified CD derivatives and their polymers were recently reported to display characteristic thermoresponsive properties and switchable inclusion abilities. − These OEG-modified CDs were further used as building blocks to construct thermoresponsive PRXs with photocontrolled degradation, − and the PRX architecture was found to play a vital role in controlling their thermoresponsive and degradable behavior. Encouraged by these works, we herein report on synthesis of slide-ring microgels from thermoresponsive diethylene glycol-modified PRXs in water through in situ cross-linking of the thermally induced aggregates above the phase transition temperatures (Figure ).…”