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<p>Oral or parenteral administration of methotrexate (MTX), a folate antagonist with strong anti-inflammatory and anticancer effects, is problematic due to systemic toxicity and poor site-specific delivery. The present study aimed to develop and optimise a MTX nanosuspension–based dry powder inhaler (DPI) for enhanced pulmonary delivery in the treatment of non-small cell lung cancer (NSCLC). MTX nanosuspensions/nanoparticle (MTX-NP) was developed using PVP-K-30 as polymer and Poloxamer-188 as a stabiliser using various methods. MTX-NP was optimised using a two-factor, three-level Central Composite Design (CCD) and characterised for entrapment efficiency (%EE), drug loading (%DL), Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X-ray diffraction (XRD), and <i>in-vitro</i> release study. The final optimised batch of Methotrexate Nanoparticles (MTX-NP) showed %EE (71.43 ± 0.31%) and %DL(5.78 ± 0.29%) and converted to MTX-DPI which showed drug content of 96.35%, optimal particle size of 2.98&#xa0;μm ± 1.51 for inhalation, highest emitted dose (%ED) of 98.74%, mass median aerodynamic diameter (MMAD) of 3.26&#xa0;μm, geometric standard deviation (GSD) of 1.68 (slightly broader than DPI 2), fine particle fraction (FPF) of 79.42%, and good flowability (Hausner ratio (HR) = 1.13 and Carr’s index (CI) = 12.26), DPI-3 (1:6 ratio) has the finest lung deposition of all. The analytical methods showed no chemical interaction between the drug and the polymer. The in vitro<i> cell line study showed dose-dependent</i> inhibition of A549 cells. The developed MTX nanosuspension-based DPI exhibited good aerosolisation characteristics and significant anticancer activity <i>in-vitro</i>, indicating its potential as an effective pulmonary delivery system for NSCLC management.</p> Graphical Abstract <p></p>

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Methotrexate Nanosuspension for Targeted Lung Cancer Therapy: Development, Optimization and Evaluation of Dry Powder Inhaler

  • 期刊论文

  • 发表日期：

    2026年3月31日

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  • Asawaree Hable,
  • Shrikant Dargude,
  • Anuruddha Chabukswar,
  • Swati Jagdale

摘要

Oral or parenteral administration of methotrexate (MTX), a folate antagonist with strong anti-inflammatory and anticancer effects, is problematic due to systemic toxicity and poor site-specific delivery. The present study aimed to develop and optimise a MTX nanosuspension–based dry powder inhaler (DPI) for enhanced pulmonary delivery in the treatment of non-small cell lung cancer (NSCLC). MTX nanosuspensions/nanoparticle (MTX-NP) was developed using PVP-K-30 as polymer and Poloxamer-188 as a stabiliser using various methods. MTX-NP was optimised using a two-factor, three-level Central Composite Design (CCD) and characterised for entrapment efficiency (%EE), drug loading (%DL), Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X-ray diffraction (XRD), and in-vitro release study. The final optimised batch of Methotrexate Nanoparticles (MTX-NP) showed %EE (71.43 ± 0.31%) and %DL(5.78 ± 0.29%) and converted to MTX-DPI which showed drug content of 96.35%, optimal particle size of 2.98 μm ± 1.51 for inhalation, highest emitted dose (%ED) of 98.74%, mass median aerodynamic diameter (MMAD) of 3.26 μm, geometric standard deviation (GSD) of 1.68 (slightly broader than DPI 2), fine particle fraction (FPF) of 79.42%, and good flowability (Hausner ratio (HR) = 1.13 and Carr’s index (CI) = 12.26), DPI-3 (1:6 ratio) has the finest lung deposition of all. The analytical methods showed no chemical interaction between the drug and the polymer. The in vitro cell line study showed dose-dependent inhibition of A549 cells. The developed MTX nanosuspension-based DPI exhibited good aerosolisation characteristics and significant anticancer activity in-vitro, indicating its potential as an effective pulmonary delivery system for NSCLC management.

Graphical Abstract