Hyaluronic acid-functionalized polypyrrole nanoparticles with controlled oxidation for targeted chemo-photothermal therapy of prostate cancer

Combined chemo-photothermal therapy as a synergistic approach has emerged to overcome the limitations of conventional chemotherapy. In this study, multifunctional polypyrrole-based nanoparticles were developed for targeted chemo-photothermal therapy of prostate cancer. In the first stage, the effect of polypyrrole backbone oxidative defects on the photothermal properties of nanoparticles was evaluated by changing the oxidant concentration during polymerization or chemical reduction of the structure post synthesis. The results showed an inverse relationship between the density of oxidative defects and the near-infrared (NIR) light absorption of the nanoparticles. To introduce active targeting capability to the system, hyaluronic acid (HA) was then conjugated onto the nanoparticle surface as a CD44-targeting ligand. Thereafter, the anticancer drug doxorubicin was loaded onto the nanoparticles, and drug release studies confirmed the photothermal responsiveness of the system. Cellular evaluations were performed on three common prostate cancer cell lines PC-3, DU145, and LNCaP, which exhibit different levels of CD44 expression. Chemotherapy alone demonstrated a significant size-dependent cytotoxic effect in CD44 positive cell lines, indicating the capability of the system for selective CD44 targeting. However, photothermal therapy induced cell death independent of CD44 expression levels. Finally, combined chemo-photothermal therapy induced a strong enhanced therapeutic effect, reducing cell viability to below 15% in all three cell lines, which represents a significant improvement compared to either treatment alone. The overall findings demonstrate the potential of the designed nanoparticles as a multifunctional platform for combined chemo-photothermal therapy of prostate cancer, particularly in the context of tumor heterogeneity and phenotypic differences among cancer cells.