Three-dimensional (3D) cell culture platforms are increasingly being used in cancer research and drug development since they mimic avascular tumors in vitro. In the present study, we focused on the development of a novel air-grown multicellular spheroid (MCS) model to mimic in vivo tumors for understanding lung cancer biology and improvement in the evaluation of aerosol anticancer therapeutics. 3D MCS were formed using A549 lung adenocarcinoma cells, comprising cellular heterogeneity with respect to different proliferative and metabolic gradients. The growth kinetics, morphology, and 3D structure of air-grown MCS were characterized by brightfield, fluorescent, and scanning electron microscopy. MCS demonstrated a significant decrease in growth when the tumor-penetrating peptide iRGD and paclitaxel (PTX) were co-administered as compared to PTX alone. It was also found that when treated with both iRGD and PTX, A549 MCS exhibited an increase in apoptosis and decrease in clonogenic survival capacity in contrast to PTX treatment alone. This study demonstrated that co-administration of iRGD resulted in the improvement of the tumor penetration ability of PTX in an in vitro A549 3D MCS model. In addition, this is the first time a high-throughput air-grown lung cancer tumor spheroid model has been developed and evaluated.

Paclitaxel (as intravenous Taxol) is one of the most applied chemotherapeutics used for the treatment of lung cancer. This project involves the development of a dry powder nanocomposite microparticle (nCmP) aerosol containing PTX-loaded nanoparticles (NP) to be delivered via a dry powder inhaler to the lungs for the treatment of non-small cell lung cancer (NSCLC). Nanoparticles were formulated by a single emulsion and solvent evaporation method, producing smooth, neutral PTX NP of approximately 200 nm in size. PTX nCmP were obtained via spray drying PTX NP with mannitol, producing amorphous wrinkled particles that demonstrated optimal aerosol deposition for in vitro pulmonary delivery. Free PTX, PTX NP, and PTX nCmP were evaluated in vitro in both 2D monolayers and 3D multicellular spheroids (MCS). PTX NP enhanced cytotoxicity when compared to pure drug in the 2D evaluation. However, on a liquid culture 3D tumor spheroid model, PTX NP and pure PTX showed similar efficacy in growth inhibition of MCS. The PTX nCmP formulation had a comparable cytotoxicity impact on MCS compared with free PTX. Finally, PTX nCmP were evaluated in an air-grown 3D MCS platform that mimics the pulmonary environment, representing a new model for the assessment of dry powder formulations.

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