Advancing Rare Cancer Therapeutics: Osimertinib-Loaded Inhaled PLGA Nanoparticles for Mesothelioma Treatment.

Despite advances in mesothelioma treatment, malignant pleural mesothelioma (MPM) continues to present a poor prognosis due to its aggressive progression and resistance to conventional therapies. Current treatment modalities, including surgery, chemotherapy, radiation, and immunotherapy, offer limited efficacy, with a five-year survival rate of approximately 12%. To address the limitations of systemic drug delivery, this study investigates the therapeutic potential of osimertinib (OSI), a third-generation tyrosine kinase inhibitor, delivered via inhalation using poly(lactic-co-glycolic acid) (PLGA) nanoparticles. The optimized PLGA-OSI formulation exhibited an encapsulation efficiency of 43.1 ± 4.8%, drug loading of 4.4 ± 0.4%, particle size of 198.5 ± 9.3 nm, and zeta potential of -17.6 ± 1.2 mV. In vitro cytotoxicity assays revealed IC₅₀ values of 13.5 ± 0.1 µM (MSTO-211H), 27.7 ± 0.3 µM (H2452), and 8.1 ± 0.2 µM (H226) after 48 h. Compared to free OSI, PLGA-OSI enhanced cellular uptake, increased GFP-positive cells by 1.7-fold, and elevated fluorescence intensity by 5.3-fold. Clonogenic and scratch assays confirmed significant inhibition of cell proliferation and migration. Moreover, spheroid models demonstrated superior tumor suppression with multi-dose treatments. These findings highlight the potential of inhaled PLGA-OSI nanoparticles to improve drug delivery and therapeutic outcomes in MPM, supporting their further development as a targeted treatment strategy against this challenging malignancy.