Pulmonary Delivery of Inhalable Sustained Release Nanocomposites Microparticles Encapsulating Osimertinib for Non-Small Cell Lung Cancer Therapy

TL;DR

This study develops an inhalable dry powder formulation of Osimertinib to treat lung cancer more effectively with less side effects.

Contribution

The first dry powder inhalation formulation of Osimertinib is developed and evaluated for lung cancer therapy.

Findings

The developed nanocomposite microparticles showed a 3.6-fold reduction in IC50 compared to free Osimertinib in A-549 cells.

The formulation exhibited excellent aerosolization properties and sustained drug release over 24 hours.

The formulation demonstrated superior antimigratory effects and enhanced cell cycle arrest in vitro.

Abstract

Background/Objective: Osimertinib (OSI) is a third-generation tyrosine kinase inhibitor approved for non-small cell lung cancer (NSCLC) therapy. OSI is administered orally; this route limits the amount of OSI reaching the tumor in the lungs and is associated with serious systemic toxicity. This study aimed to develop a dry powder inhalable formulation to provide tumor-targeted delivery and minimize systemic toxicity. To the best of our knowledge, this is the first study to prepare and evaluate a dry powder inhalation formulation of OSI. Methods: Chitosan-coated PLGA nanoparticles (PLGA-C NPs) encapsulating OSI were prepared using a single emulsion-solvent evaporation technique. PLGA-C NPs were assembled into respirable nanocomposite microparticles (NCMPs) via spray drying with L-leucine as a carrier. PLGA-C NPs were characterized for particle size, zeta-potential, encapsulation efficiency, and in vitro efficacy in A-549 cell line. NCMPs were evaluated for solid-state properties, aerosolization performance, stability and in vitro release. Results: PLGA-C NPs exhibited a particle size of 145.18 ± 3.0 nm, high encapsulation efficiency and a positive zeta potential. In vitro studies demonstrated a 3.6-fold reduction in IC50 compared to free OSI, superior antimigratory effects and enhanced cell cycle arrest. Solid-state characterization of NCMPs demonstrated drug encapsulation in the polymer without chemical interaction. NCMPs exhibited excellent aerosolization (mass median aerodynamic diameter of 1.09 ± 0.23 μm, fine particle fraction of 73.48 ± 8.6%) and sustained drug release (61.76 ± 3.9% at 24 h). Stability studies confirmed the physicochemical stability integrity. Conclusions: These findings suggest that this novel dry powder inhalable OSI formulation may improve therapeutic outcomes while reducing systemic toxicity.

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