Phospholipid End-Capped Bioreducible Polyurea Micelles as a Potential Platform for Intracellular Drug Delivery of Doxorubicin in Tumor Cells

Abstract

Bioreducible polymeric nanocarriers bearing disulfide bonds have been widely used for intracellular therapeutic delivery, since they are quickly sliced or reduced in the reductive milieu of cytosol. Incorporation of hydrophobic phospholipid analogues to polymers improves the biocompatibility by reducing the protein adsorption and platelet adhesion on the cell membranes. In this study, we have developed a series of bioreducible polyureas (PUs) bearing disulfide linkages in their backbone and phospholipid moieties in their chain ends. The reducible PUs exhibit interesting self-assembly behavior and controlled release profiles at intracellular mimic conditions. The self-assembled hybrid nanocarriers with an average diameter of about 110 nm efficiently encapsulated the model anticancer drug doxorubicin (Dox). The in vitro Dox release profile demonstrated a good glutathione (GSH)-responsive release of Dox at 10 mM GSH. An in vitro cell viability assay was also performed with various cell lines. The antitumor activity tests using HCT15 and HCT116 cancer cells showed that Dox-loaded nanocarriers bearing disulfide linkages induced significantly higher cytotoxicity in cancer cells than those without disulfide linkages. Hence, the PU nanocarriers bearing disulfide linkers and α,ω-phospholipid moieties have a promising potential to trigger the drug into the intracellular compartment of cancer cells.

One‐step formation of polyurea gel as a multifunctional approach for biological and environmental applications

“…Polyurethane and polyureas (PUs) are a class of polymers that display elastomeric, thermoplastic and thermoset behaviors depending on their chemical and morphological composition . These polymers have been used in a wide range of applications as scaffolds/implants in tissue engineering, drug delivery systems, foams, paints and coatings, adhesives, smart hydrogels etc. In particular, PU elastomers can be easily synthesized by reacting an isocyanate (N=C=O) with an amine (NH 2 ) (to form urea groups) through a step growth polymerization process, which presents hard domains randomly dispersed within soft domains, forming a heterogeneous landscape with a nano‐segregated microstructure .…”

PEGylated Polyurea Bearing Hindered Urea Bond for Drug Delivery

“…Furthermore, the hydrolyzability can be regulated by changing the units of polyureas [5]. Due to their excellent hydrolyzability and biocompatibility, polyureas have been developed for biomedical applications, including drug delivery [6,7,8].…”

“…The nanoplatforms based on biotinylated polyurethane-ureas were potentially used for the therapy of other types of cancer. John et al synthesized a series of polyureas with disulfide linkages in the backbone, and the antitumor drug DOX was encapsulated by the nanocarriers [7]. The drug-loaded nanocarriers demonstrated the glutathione-responsive drug release behavior, indicating significant potential for controlled drug delivery.…”

PEGylated Polyurea Bearing Hindered Urea Bond for Drug Delivery

“…The nanoplatforms based on biotinylated polyurethane-ureas were potentially used for the therapy of other types of cancer. John et al synthesized a series of polyureas with disulfide linkages in the backbone, and the antitumor drug DOX was encapsulated by the 2 of 14 nanocarriers [11]. The drug-loaded nanocarriers demonstrated the glutathione-responsive drug release profile, indicating great potential for controlled drug delivery.…”