Drug development and industrial pharmacy · 2026
Rutin-enabled improved systemic exposure of doxorubicin via nanostructured lipid carriers: a proof of concept through novel LC-MS/MS analysis.
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Agarwal Neha, Bakshi Avijit Kumar, Panwar Dilip, Santosh Patil Rohit, Mishra Prabhat Ranjan
Аннотация
OBJECTIVE: The objective of this study was to develop and validate a sensitive LC-MS/MS method for simultaneous quantification of doxorubicin (DOX) and rutin (RUT) in plasma and to apply it as a proof-of-concept to investigate rutin-enabled enhancement of systemic DOX exposure via nanostructured lipid carriers (NLCs).
SIGNIFICANCE: Poor oral bioavailability and dose-limiting toxicity restrict the clinical utility of DOX. Co-delivery with RUT, a bioactive flavonoid known to improve drug absorption and therapeutic response, may overcome these limitations. A robust bioanalytical strategy is essential to evaluate such combination-based nanotherapeutic systems.
METHODS: A simultaneous LC-MS/MS method was developed and validated in rat plasma in accordance with ICH guidelines. Dual drug-loaded NLCs were prepared using an emulsification-sonication technique and optimized through a Quality-by-Design approach. The optimized NLCs were characterized for particle size, polydispersity index and zeta potential. In vitro cytotoxicity was evaluated in MDA-MB-231 breast cancer cells, followed by pharmacokinetic studies in rats.
RESULTS: The validated method demonstrated excellent linearity, accuracy, precision, recovery, minimal matrix effects, absence of carryover, acceptable stability and robustness. Optimized NLCs exhibited a particle size of 171.27 ± 0.45 nm, a PDI of 0.28 ± 0.01, and a zeta potential of -23.53 ± 0.38 mV. Combination delivery of DOX and RUT resulted in a two-fold reduction in IC50 values compared with individual drugs. Pharmacokinetic analysis revealed a nearly three-fold increase in DOX AUC0-t compared with free DOX.
CONCLUSION: Rutin-enabled NLCs significantly enhance the systemic exposure and therapeutic performance of DOX, validated through a novel simultaneous LC-MS/MS bio-analytical approach.
SIGNIFICANCE: Poor oral bioavailability and dose-limiting toxicity restrict the clinical utility of DOX. Co-delivery with RUT, a bioactive flavonoid known to improve drug absorption and therapeutic response, may overcome these limitations. A robust bioanalytical strategy is essential to evaluate such combination-based nanotherapeutic systems.
METHODS: A simultaneous LC-MS/MS method was developed and validated in rat plasma in accordance with ICH guidelines. Dual drug-loaded NLCs were prepared using an emulsification-sonication technique and optimized through a Quality-by-Design approach. The optimized NLCs were characterized for particle size, polydispersity index and zeta potential. In vitro cytotoxicity was evaluated in MDA-MB-231 breast cancer cells, followed by pharmacokinetic studies in rats.
RESULTS: The validated method demonstrated excellent linearity, accuracy, precision, recovery, minimal matrix effects, absence of carryover, acceptable stability and robustness. Optimized NLCs exhibited a particle size of 171.27 ± 0.45 nm, a PDI of 0.28 ± 0.01, and a zeta potential of -23.53 ± 0.38 mV. Combination delivery of DOX and RUT resulted in a two-fold reduction in IC50 values compared with individual drugs. Pharmacokinetic analysis revealed a nearly three-fold increase in DOX AUC0-t compared with free DOX.
CONCLUSION: Rutin-enabled NLCs significantly enhance the systemic exposure and therapeutic performance of DOX, validated through a novel simultaneous LC-MS/MS bio-analytical approach.