Abstract 1807: Distribution, fate, inhalation exposure of nanoparticles: advancing noninvasive strategies for lung cancer treatment

Abstract Background: Lung cancer remains the leading cause of cancer-related morbidity and mortality worldwide, including in the United States. Noninvasive nebulized inhalation represents a promising therapeutic strategy for lung cancer, offering enhanced nanoparticle targeting efficiency and prolonged retention within lung tissue. Gambogic acid is an experimental chemotherapeutic agent for lung cancer. Suboptimal biodistribution, and multi-targeting properties can lead to significant systemic toxicity challenges. To mitigate these undesirable side effects and improve clinical translation, nanotechnology-based strategies offer a promising solution. This study aims to develop inhalable nanoparticles (INPs) for effective delivery of therapeutic agents in lung cancer cell lines and in-vivo models. Methods: INPs were synthesized via solvent evaporation and self-assembly and characterized for particle size, drug loading efficiency, and drug release using various analytical methods. Their cellular uptake, intracellular distribution, and colocalization efficacy of INPs were assessed in 2D and 3D lung cancer cell line (A549 and NCI-H1299) models using flow cytometry and confocal microscopy. The fate and biodistribution of INPs were monitored using live animal imager at 24 and 48 hrs post-treatment. The accumulation of INPs in lung tissue was evaluated using in vivo, ex vivo, and microscopy methods. The therapeutic efficacy evaluation of gambogic acid encapsulated INPs was evaluated through in vitro assays, using cell proliferation, clonogenicity, migration, and apoptosis assays. Results: The developed INPs exhibited an average size of approximately 110 nm based on dynamic light scattering measurements. These formulations exhibited notable mucoadhesion and mucopenetration potential in-vitro models. Drug release experiments displayed a sustained and higher drug release at lysosomal pH (pH 5.0) compared to pH environment (pH 7.4), attributed to the pH-sensitive bonding. The gambogic loaded INPs were confirmed to have superior inhibitory effects on cellular proliferation, colony formation, and migratory characteristics of lung cancer cells. Biodistribution analysis of INPs in mice demonstrated that the particles were predominantly concentrated in lung tissues, with minimal distribution to other organs. Immunohistochemistry and blood chemistry analyses indicate that the INPs possess biologically safe properties. Conclusions: This study confirms the potential of INPs a novel therapeutic modality for lung cancer treatment. The INPs formulation demonstrated superior therapeutic benefits, including improved drug delivery, enhanced cellular uptake, and increased anti-cancer efficacy across various lung cancer models. These findings suggest that INPs could serve as an innovative therapeutic modality for the treatment of lung cancer. Citation Format: Rahul Tiwari, Meghana Kolli, Neeraj Chauhan, Eswara N Ghali, Iris Enriquez, Vivek Kumar Kashyap, Subhash Chauhan, Murali Yallapu. Distribution, fate, inhalation exposure of nanoparticles: advancing noninvasive strategies for lung cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1807.