pH/redox responsive size‐switchable intelligent nanovehicle for tumor microenvironment targeted DOX release

Abstract

Tumor microenvironment (TME) targeted strategy could control the drug release in tumor cells more accurately and creates a new opportunity for enhanced site-specific targeted delivery. In this study, (PAA-b-PCL-S-S-PCL-b-PAA) copolymeric nanoparticles (NPs) with size-switchable ability and dual pH/redox-triggered drug release behavior were designed to significantly promote cancer uptake (cell internalization of around 100% at 30 min) and site-specific targeted doxorubicin (DOX) delivery in MDA-MB-231 tumor cells. NPs surface charge was shifted from − 17.8 to − 2.4 and their size shrunk from 170.3 to 93 nm in TME. The cell cycle results showed that DOX-loaded NPs showed G2/M (68%) arrest, while free DOX showed sub-G1 arrest (22%). Apoptosis tests confirmed that the cells treated with DOX-loaded NPs showed a higher amount of apoptosis (71.6%) than the free DOX (49.8%). Western blot and RT-PCR assays revealed that the apoptotic genes and protein levels were significantly upregulated using the DOX-loaded NPs vs. the free DOX (Pvalue < 0.001). In conclusion, dual pH/redox-responsive and size-switchable DOX-loaded NPs developed here showed outstanding anti-tumoral features compared with free DOX that might present a prospective platform for tumor site-specific accumulation and drug release that suggest further in vivo research.

Evolution of Hybrid Hydrogels: Next-Generation Biomaterials for Drug Delivery and Tissue Engineering

“…For the targeted delivery of anticancer agents to tumor cells, redox/enzyme and redox/pH-responsive carriers are also advantageous [242,243]. Specifically, self-assembled nanoparticles featuring redox-sensitive bonds can release docetaxel triggered by hyal-1 and glutathione, leveraging lysosomal enzyme hydrolysis and reducing the agent degradation of disulfide bonds [244].…”