Synergistic Anticancer Potential of Andrographolide and Paclitaxel: A Dose-Reduction Strategy to Minimize Toxicity and Enhance Therapeutic Efficacy

Objective: To study the synergistic anticancer efficacy of Andrographolide (AG), a bioactive phytochemical with immunomodulator properties, and paclitaxel (PTX), a frontline chemotherapeutic agent, when administered as co-loaded nanoemulsion, to enhance therapeutic outcome with minimal adverse effect.Significance: The proposed nanoemulsion is expected to achieve synergistic anticancer effects, and minimize systemic toxicity.Key findings: Cytotoxic potential of AG and PTX at various molar concentrations using Chou-Talalay method were determined. A synergistic ratio (1:1) was identified and used as coloaded nanoemulsion. The system was optimized for particle size, zeta potential and encapsulation efficiency. Thermal and spectral characterization techniques were employed to evaluate drug identity and compatibility, while HPLC-based analytical method was developed for simultaneous quantification of AG and PTX in % entrapment and drug release samples. Further evaluated for MTT test, cell uptake study, scratch migration test, apoptosis and cell cycle arrest. Tumour regression test confirmed therapeutic efficacy and acute toxicity test ensure the safety of developed formulation. The AG-PTX nanoemulsion exhibited enhanced cellular uptake, cell apoptosis, and cell-cycle arrest in vitro compared to monotherapies. In vivo studies using a syngeneic tumour (invasive mammary carcinoma) bearing mouse model demonstrated significant tumour regression (10-fold), improved and reduced systemic toxicity, as shown by stable body weight and histopathological assays.Conclusion: Co-delivery of AG and PTX via targeted nanocarrier offers a promising dose reduction strategy to circumvent the dose limiting toxicity of PTX while maintaining/enhancing its anticancer efficacy. Further, the findings suggest a translational potential for AG as a chemosensitizer in combination therapy regimens.