QbD-based co-loading of paclitaxel and imatinib mesylate by protamine-coated PLGA nanoparticles effective on breast cancer cells

<b>Aim:</b> Paclitaxel and imatinib mesylate are drugs used in the treatment of breast cancer. Conventional drug-delivery systems have limitations in the effective treatment of breast cancer using the drugs. <b>Materials &amp; methods:</b> Combination index studies were used to identify the optimum ratio of both drugs showing maximum synergistic effect. Using a systematic quality-by-design approach, protamine-coated PLGA nanoparticles co-loaded with paclitaxel and imatinib mesylate were formulated. Further characterization and cell line evaluations were performed. <b>Results:</b> Encapsulation efficiency obtained was 92.54% for paclitaxel and 75.12% for imatinib mesylate. A sustained (24 h) and controlled zero-order drug release was obtained. <b>Conclusion:</b> Formulated nanoparticles had a low IC₅₀ value and enhanced cellular uptake. Paclitaxel and imatinib (PXL and IMA) show synergistic efficacy against the MCF-7 cell line of breast cancer. PXL and IMA in the ratio of 4:1 show maximum effect and lowest combination index (CI). Quality-by-design methodology led to optimization and systematic formulation of coloaded protamine-coated PLGA nanoparticles. Protamine decreased the initial burst release of the formulations. A sustained zero-order drug release was obtained for both the formulations. Protamine coating was clearly visible on images using transmission electron microscopy analysis. Significant reduction in IC₅₀ values showing increased cytotoxicity was observed. Roughly 30-fold increase in cellular uptake was obtained as compared with free drugs.