Engineered Spray-Dried PLGA-PEG Dual-Coated Micelles with Lactose/Trehalose Matrices for Pulmonary Doxorubicin Delivery: Achieving Sustained Release and Improved Aerosol Performance in NSCLC Therapy

Abstract Background Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality. Intravenous doxorubicin (DOX) is effective but limited by severe cardiotoxicity and poor lung tumor selectivity. Objective To develop an inhalable dry powder inhaler (DPI) of DOX-loaded PLGA-PEG dual-coated micelles embedded in a lactose/trehalose matrix for targeted pulmonary delivery and reduced systemic toxicity. Methods Micelles were prepared via nanoprecipitation and engineered into respirable powders via spray-drying. Formulations were characterized for size, stability, aerosol performance, drug release, and cytotoxicity (SLC cells). In vivo pharmacokinetics, lung deposition, antitumor efficacy, and systemic safety were assessed in rat models. Results Optimized micelles showed high encapsulation efficiency (91.3%), desirable aerodynamic properties (MMAD 2.9 µm, FPF 62.4%), and sustained biphasic release. They significantly enhanced cytotoxicity (IC₅₀ 1.82 vs. 3.96 µg/mL) and apoptosis (48.6% vs. 29.7%) compared to free DOX. In vivo, pulmonary delivery achieved 46.8% lung retention at 24 h (vs. 12.4%), prolonged systemic residence time (MRT 14.7 h vs. 6.1 h), and superior tumor growth inhibition (68.5% vs. 25.3%). Critically, micellar DOX markedly reduced cardiotoxicity (CK-MB ↓55%, LDH ↓48%) with minimal histopathological cardiac damage. Conclusion The spray-dried micellar DPI platform enables efficient lung-targeted delivery of DOX, enhancing antitumor efficacy while mitigating systemic cardiotoxicity, presenting a promising therapeutic strategy for NSCLC.