Co-Spray Dried Mannitol/Poly(amidoamine)-Doxorubicin Dry-Powder Inhaler Formulations for Lung Adenocarcinoma: Morphology, In Vitro Evaluation, and Aerodynamic Performance.

nhaled chemotherapeutics have emerged as a promising regimen to combat lung cancer as they maximize local drug concentration while significantly reduce systemic exposure. However, the poor lung/systemic safety profiles and lack of clinically efficient formulations restrict the applicability of inhaled chemotherapeutics. This work developed a dry-powder inhaler (DPI) formulation that dispersed a pH-responsive poly(amidoamine) dendrimer-doxorubicin conjugate (G4-12DOX) into mannitol microparticles. The dendrimer conjugate only releases cytotoxic agents in response to intracellular pH drop, leading to reduced systemic and local toxicity. This work investigated the effect of G4-12DOX content on the microparticle size and morphology, redispersibility, in vitro cytotoxicity, and aerosol properties of the formulations. The spray-dried G4-12DOX/mannitol microparticles showed smooth and spherical morphology with 1-4 μm in diameter. As the content of the G4-12DOX conjugate in the microparticles increased, the size, and degree of aggregation of microparticles increased dramatically. The G4-12DOX/mannitol microparticles were readily redispersed in the aqueous environment, reverting to nanoscale dendrimer conjugates to escape alveolar phagocytosis. All DPI formulations demonstrated the similar cytotoxicity as the original conjugate against a lung adenocarcinoma cell line. The emitted dose (ED) and fine particle fraction (FPF) of the DPI formulations decreased as the content of G4-12DOX increased, but EDs and FPFs of all formulations fell within the range of 85-60% and 60-40%, which were higher than those of commercial products (EDs = 40-60%; FPFs = 12-40%). Therefore, the spray-dried dendrimer/mannitol microparticle is an efficient and practical DPI formulation for direct delivery of large dose of chemotherapeutics to lung tumors.