pH-Responsive Hyaluronic Acid Nanoparticles for Enhanced Triple Negative Breast Cancer Therapy

Purpose: This study emphasized that dasatinib (DAS) and olaparib (OLA) have synergistic effects on triple negative breast cancer, by inducing DNA damage and inhibiting DNA damage repair. However, poor water solubility, short half-life of drugs, and low drug concentration in tumor tissue limit the clinical application. Methods: In this research, acid-sensitive ester bonds were used to connect hydrophobic DAS and hydrophilic hyaluronic acid (HA) to form the amphiphilic polymer prodrug HA-DAS, and then OLA was added as the core, the HA-DAS was used as the carrier to form nanomicelles (HDO-NPs) in aqueous. The characterization and drug release of HDO-NPs were studied, and the cytotoxicity, targeting effect, and intracellular transport behavior of HDO-NPs were evaluated in MDA-MB-231. In addition, the pharmacokinetic and therapeutic effect of HDO-NPs were further verified in vivo. Results: In vitro characterizations showed that HDO-NPs were spherical with uniform particle size, good stability and anti-dilution ability, and displayed favorable pH-responsive drug release behavior. In addition, the cell experiments showed that HDO-NPs could be effectively taken up by binding to the overexpressed CD44 proteins of MDA-MB-231 cells, resulting in increased intracellular drug concentration. In vivo experiments showed that HDO-NPs can effectively target tumor tissues, have excellent therapeutic effects on tumor, significantly prolong the circulation time of drugs in vivo, and effectively improved the bioavailability of drugs. Conclusion: DAS and OLA were designed into micelles, the efficacy of HDO-NPs was higher than that of free drugs. Therefore, HDO-NPs have good application prospects in the treatment of triple negative breast cancer. Keywords: hyaluronic acid, dasatinib, olaparib, combination therapy, polymeric prodrug micelles