Hyaluronic acid functionalized liposomes for co-delivery of paclitaxel and ursolic acid for enhanced efficacy against triple negative breast cancer

Triple negative breast cancer (TNBC) stands out as an aggressive and lethal subtype of breast cancer. Despite being a mainstay in treatment, the efficacy of paclitaxel (PTX) diminishes due to significant tumor heterogeneity and emergence of drug resistance. Combination drug therapy stands out as the foremost strategy for addressing these limitations. Therefore, the current study aimed to develop hyaluronic acid (HA) modified liposomes for tumor targeted co-delivery of PTX with UA, a phytocompound with potent antitumor properties, with the goal of achieving an enhanced chemotherapeutic response. The PTX and UA co-loaded cationic liposomes (PTX/UA-CatLip) were prepared via thin film hydration using Leciva S90:DOTAP:cholesterol (5:3:2 M ratio), followed by HA coating through electrostatic interactions. The PTX/UA-HA-Lip exhibited a spherical shape, a particle size of 108 nm, a PDI of 0.27, and a zeta potential of -14.5 mV, with encapsulation efficiency of 82.56 % for PTX and 77.27 % for UA. These liposomes exhibited biphasic drug release, with cumulative PTX and UA release of 79.66 % and 73.26 %, respectively, over 72 h. The PTX/UA-HA-Lip demonstrated enhanced cellular uptake in MDA-MB-231 and 4T1 cells attributed to HA-CD44 interaction. PTX/UA-HA-Lip showed lower IC50 value, higher apoptotic index, increased ROS generation, and mitochondrial depolarization in MDA-MB-231 and 4T1 cells. In vivo, PTX/ UA-HA-Lip demonstrated 2.28- and 2.54-fold higher AUC, 2.79- and 3.69-fold longer t1/2, and 2.55- and 3.36fold longer MRT compared to free PTX and UA, respectively, with significant tumor volume reduction in the 4T1-based TNBC model. Toxicity assessment revealed no significant elevation in serum toxicity biomarkers and no observable damage to the body organs, demonstrating its safety.