Unleashing the Potential of 6-Mercaptopurine: Microemulsion Innovations for Enhanced Oral Bioavailability and Therapeutic Impact

Introduction: 6-Mercaptopurine (6-MP) is an anticancer agent that disrupts cancer cell growth, ultimately causing cell death. It is classified as a BCS Class II drug, indicating poor aqueous solubility and limited oral bioavailability. To reduce these problems, nanocarriers have been prepared, which are non-toxic, biodegradable, and biocompatible. Methods: The 6-MP loaded microemulsion has been formulated and characterized for physicochemical characterization, morphology, drug content, and release study. The cell line studies were implemented on the MDA-MB-231 cell line for cell viability and cellular uptake analysis. Results: The optimized formulation (ME4) exhibited a droplet size of 115.47 ± 1.53 nm, entrapment efficiency of >90%, and a stable physicochemical profile. It demonstrated sustained drug release and significantly higher cellular uptake with an IC50 value of 2.17 ± 0.21 μM, compared to 3.87 ± 0.11 μM for free 6-MP. Ex-vivo permeation studies showed 80% drug permeation within 120 minutes versus 42% for pure 6-MP. Invivo pharmacokinetics revealed a 1.79-fold increase in oral bioavailability compared to the marketed tablet. XO inhibition studies confirmed ME4’s role in reducing presystemic metabolism, with 59.60 ± 2.25% inhibition at 200 μg/mL, comparable to the standard inhibitor allopurinol (73.42 ± 2.34%). Discussion: The developed microemulsion successfully addresses the dual challenge of poor solubility and extensive first-pass metabolism of 6-MP, resulting in significantly enhanced bioavailability and anticancer activity. These findings highlight its potential for future clinical development as a novel oral delivery platform for cancer therapy. Conclusion: The results demonstrate the future potential of 6-MP as a successful nanotherapeutic agent for cancer treatment that is more effective and safer.