article · Advanced Pharmaceutical Bulletin
A polymeric micelle delivery system was developed to co-load the chemotherapy agent temozolomide and n-acetylcysteine to evaluate their combined effect against human glioblastoma multiforme A172 cells. Six initial formulations were prepared using different ratios of pluronic polymers, with an eighty-to-twenty ratio identified as optimal for drug loading. Subsequent testing of eight co-loaded variants identified three candidate formulations that significantly reduced the half-maximal inhibitory concentration. Detailed evaluation of the leading candidate formulation showed nanoscale particle sizes, stable surface charge, and confirmed encapsulation of both active agents. This formulation achieved a 1.783-fold improvement in temozolomide dissolution efficiency compared to the pure drug. Furthermore, cellular uptake increased by thirty-fold for temozolomide and fifteen-fold for n-acetylcysteine relative to the free compounds. Analysis of cell cycle arrest and apoptosis demonstrated synergistic cytotoxic action against the glioblastoma cell line.
Glioblastoma multiforme is an aggressive brain cancer where standard chemotherapy often faces challenges with drug delivery and cellular uptake. Combining temozolomide with n-acetylcysteine in a single nanoscale carrier improves the dissolution and cellular entry of both substances. Demonstrating synergy between these compounds in cell culture helps researchers investigate more effective formulation strategies for cancer therapies.
This formulation serves as an early-stage drug delivery candidate for oncology therapeutics, specifically targeting glioblastoma multiforme. The primary users would be pharmaceutical formulation scientists and nanomedicine developers seeking improved delivery systems for poorly soluble cancer drugs. Because all evaluations were restricted to in vitro laboratory testing on a single cell line, the technology remains at an early discovery stage, requiring extensive preclinical animal testing and clinical evaluation before real-world use.
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Purpose: The aim of this study was to develop TMZ-NAC loaded polymeric micelles (TNPM), evaluate them in vitro, and study the synergistic effect between Temozolomide (TMZ) and N-acetylcysteine (NAC) on the human glioblastoma multiforme A172 cell line (HGM-A172). Methods: Six (TNPM) formulations (F1 to F6) were fabricated by pluronic p-123 (P123) and pluronic p-188 (P188) at different molar percentages using a modified thin-film hydration method. The formula F5 provided the highest percentage of drug loading for TMZ and NAC. Thus, different ratios of the two drugs were loaded in polymeric micelles (PM) with molar percentage (80:20) of P123:P188 to form eight TNPM formulations (L1 to L8) that were evaluated for cytotoxic effect against (HGM-A172). Results: TNPM formulations (L2, L3 and L4) provided the lowest IC50 (31.5±0.38 mg/ml, 19.94±0.15 mg/ml and 18.3±0.21 mg/ml, respectively). Furthermore, Characterization of the selected (L2 and L4) was done. Moreover, the formula (L4) was selected according to the previous characterization for in vitro release studies, cell cycle analysis, cell apoptosis and cellular uptake. The L4 showed an average particle size 25.39±10.31 nm and zeta potential -24.5±4.8 mV. The DSC and FT-IR analysis confirmed the encapsulation of both drugs within PM. TNPM (L4) provided a 1.783-fold increase in the dissolution efficiency (%) of TMZ, compared to pure TMZ. The cellular uptake efficiency after 24 h was 30.48 and 15 folds higher than the free TMZ and free NAC, respectively. Conclusion: The combination index calculation, cell cycle analysis and cell apoptosis confirmed the cytotoxic synergistic effect between TMZ and NAC in L4 against (HGM-A172).
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DOI: 10.34172/apb.47566
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