Bioinformatics-Driven Engineering of ROS-Responsive Dextran--Poly(propylene sulfide) Nanoparticles Functionalized with Folic Acid for Targeted Prostate Cancer Therapy.

Prostate cancer (PCa) remains a significant challenge in oncology due to its complex pathogenesis and resistance to conventional therapies. By leveraging bioinformatics-guided insights, we identified folate hydrolase 1 (FOLH1) as a crucial biomarker with overexpression in various cancers, particularly PCa. Therefore, we prepared folate receptor-targeted reactive oxygen species (ROS)-responsive dextran--poly-(propylene sulfide) nanoparticles to enhance targeted therapeutic efficacy against PCa. The block copolymer was achieved using Cu-(I)-catalyzed "click" chemistry, followed by the successful conjugation of folic acid (FA). Characterization confirmed the nanoparticles' ability to encapsulate doxorubicin (Dox) and respond to ROS, releasing the drug under oxidative conditions. In vitro studies demonstrated enhanced cellular uptake, increased ROS production, and superior cytotoxicity of FA-Dex--PPS-Dox in PC3 cells compared to free Dox and nontargeted Dex--PPS-Dox nanoparticles. Furthermore, FA-Dex--PPS-Dox significantly inhibited tumor cell migration and invasion, emphasizing its potential for comprehensive cancer therapy. In vivo efficacy was assessed using a PC3 tumor model, where FA-Dex--PPS-Dox notably reduced tumor volume and weight, with histological analyses confirming enhanced apoptosis and reduced cell proliferation. These findings underscore the promising potential of FA-Dex--PPS-Dox in providing a targeted, ROS-responsive therapeutic strategy for prostate cancer.