IN VITRO CYTOTOXICITY OF FUNCTIONALIZED LIPID NANOPARTICLES DESIGNED FOR THE ENCAPSULATION OF PACLITAXEL

Breast cancer (BC) constitutes a significant public health concern, being the most frequent and the second most lethal malignancy among women, worldwide. Chemotherapy remains the pillar of clinical BC treatment, with taxanes and anthracyclines being the primary agents used. However, the toxicity and severe side effects associated with these therapies present substantial challenges in the conventional treatment of BC. Cannabidiol (CBD), an endocannabinoid, has been investigated for its antitumor properties. However, its clinical applicability is hindered by low aqueous solubility, limited bioavailability, and susceptibility to oxidation. Drug delivery systems (DDS) are interesting tools to address such limitations. Therefore, the aim of this study was to develop nanostructured lipid carriers (NLC) as DDS for the co-encapsulation of the taxane paclitaxel (PTX) and CBD aiming to achieve sustained release and to reduce the toxicity of BC treatments. Additionally, the antioxidant α-tocopherol (5%) was incorporated into the formulation. The stability of the developed formulation (NLC-CBD-PTX) was followed for 6 months showing: a homogenous population (PDI <0.2) of ca. 6 x 1013 particles/mL, sizes in the range of 220 nm, negative Zeta potentials (-28.7 mV), spherical morphology and high encapsulation efficiency (99% for both PTX and CBD). Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analyses were used to further characterize the formulation. The effect of NLC-CBD-PTX on murine breast carcinoma cells (4T1-luciferase) and normal fibroblasts (NIH-3T3) in culture was evaluated over 24 hours. Free CBD exhibited cytotoxicity in both cell lines (IC50 values = 0.009 and 0.08% for tumor and normal cells, respectively). While NLC-CBD (control nanoparticles) showed toxicity only at concentrations above 1010 particles/mL (IC50 = 6.1 and 9.5x1010 particles/mL for tumor and normal cells respectively), the NLC-CBDPTX demonstrated greater cytotoxicity than the reference drug Taxol ®. Additionally, it was more specific to tumor cells (IC50 = 0.34 and 1.1 µM for NLC-CBD-PTX and Taxol®, respectively) than to normal cells (IC50 = 6.3 and 75.6 µM, respectively). These results indicate a promising pathway for the developed nanoformulation in the treatment of BC, with the potential to improve the quality of life for patients who need to undergo aggressive therapies for tumor remission.