Bioreducible Polymer Nanocarrier Based on Multivalent Choline Phosphate for Enhanced Cellular Uptake and Intracellular Delivery of Doxorubicin

Abstract

Limited cellular uptake and inefficient intracellular drug release severely hamper the landscape of polymer drug nanocarriers in cancer chemotherapy. Herein, to address these urgent challenges in tumor treatment simultaneously, we integrated the multivalent choline phosphate (CP) and bioreducible linker into a single polymer chain, designed and synthesized a neoteric bioreducible polymer nanocarrier. The excellent hydrophility of these zwitterionic CP groups endowed high drug loading content and drug loading efficiency of doxorubicin to this drug delivery system (∼22.1 wt %, ∼95.9%). Meanwhile, we found that the multivalent choline phosphate can effectively enhance the internalization efficiency of this drug-loaded nanocarrier over few seconds, and the degree of improvement depended on the CP density in a single polymer chain. In addition, after these nanocarriers entered into the tumor cells, the accelerated cleavage of bioreducible linker made it possible for more cargo escape from the delivery system to cytoplasm to exert their cytostatic effects more efficiently. The enhanced therapeutic efficacy in various cell lines indicated the great potential of this system in anticancer drug delivery applications.

Hydrogen Peroxide and Glutathione Dual Redox‐Responsive Nanoparticles for Controlled DOX Release

“…Once oxidized by H 2 O 2 , the phenylboronic ester self‐immolative leaving group will be activated and decomposed quickly into p ‐quinone methide via the sequential 1,6‐elimination reaction . On the other hand, cancer cells maintain reducing conditions due to the elevated intracellular GSH levels (2–10 m m GSH) compared to extracellular environment (2–20 µ m GSH) . Polymers constructed with disulfide bonds are commonly used to design nano‐drugs, which characterized with disulfide linkages in micellar cores or at interfaces between cores and coronas .…”

Computational insights of two‐dimensional infrared spectroscopy under electric fields in phosphorylcholine

“…Phosphorylcholine is a precursor of the neurotransmitter acetylcholine, which is involved in many biological and cellular many functions, including memory and cell control, as well as cutting off nerve integrity and signaling . Liu et al demonstrated that Zn 2+ could cause significant aggregation or fusion of Phosphorylcholine liposomes and emphasized that coated nanomaterials could improve their biocompatibility and drug binding efficiency. Phosphorylcholine and phospholipids have good emulsifying properties, which prevent cholesterol from deposition on the inner wall of blood vessels .…”

Cell‐Membrane‐Targeted Drug Delivery System Based on Choline‐Phosphate‐Functionalized β‐Cyclodextrin

“…[1] They can improve the water solubility, loading efficiency, and biocompatibility of various hydrophobic drugs; so, they are widely used as pharmaceutical cell internalization, and improve therapy efficacy. [26] Thus, we hypothesize that the modification of β-CD with the CP group may simultaneously improve its water solubility and enhance the cellular uptake efficiency.…”