Enhanced Anticancer Activity of Ibuprofen and 2′-Hydroxy-2,3,5′-trimethoxychalcone-Linked Polymeric Micelles in HeLa Cells

Cervical cancer (CVC) remains one of the most prevalent gynecological malignancies, necessitating the development of more effective therapeutic strategies to reduce tumor burden and prevent metastasis or recurrence. Conventional chemotherapy often causes severe side effects such as myelosuppression and leukopenia. This study aimed to develop a novel nanoparticle-based formulation to improve anticancer efficacy while minimizing toxicity. We synthesized a polymeric micelle formulation incorporating (S)-ibuprofen ((S)-IP) and 2'-hydroxy-2,3,5'-trimethoxychalcone (DK143), termed (S)-IP-DK143 NP. <i>In vitro</i> cytotoxicity assays were performed in HeLa cervical cancer cells. Mechanistic studies included intracellular reactive oxygen species (ROS) detection, analysis of mitochondrial dynamics, and assessment of mitogen-activated protein kinase (MAPK) pathway activation. Nanoparticle uptake was visualized using fluorescence microscopy. (S)-IP-DK143 NP demonstrated superior anticancer activity compared to the non-nanoparticle formulation, significantly reducing the IC₅₀ value in HeLa cells. The formulation induced ROS-mediated apoptosis, disrupted mitochondrial dynamics, and activated MAPK signaling, particularly via p38 phosphorylation. Fluorescence imaging confirmed rapid nanoparticle uptake within 1 h, suggesting efficient intracellular delivery. Our findings suggest that (S)-IP-DK143 NP enhances drug bioavailability and cytotoxicity through targeted delivery and ROS-mediated apoptotic signaling. The combination of pH-sensitive polymeric micelles and chalcone-based chemotherapy represents a promising approach for cervical cancer treatment. Further preclinical and clinical studies are warranted to validate its potential as an injectable anticancer formulation.