The aerosolization process does not affect the cytotoxic effect of the chemotherapy as shown by similar levels of growth inhibition with nebulized and nonnebulized GEM in NCI-H460 and A549 NSCLC cell lines (Gagnadoux et al. 2006). In vivo efficacy of aerosol chemotherapy has been evaluated in mouse models for lung metastasis treated with inhaled liposomal 9-NC (Koshkina et al. 2000), inhaled GEM (Koshkina and Kleinerman 2005), or inhaled liposomal paclitaxel (Koshkina et al. 2001). Another murine model found that weekly inhalation of GEM achieved complete or partial inhibition of tumor growth after intrabronchial implantation of large cell undifferentiated primary lung cancer cells (NCI-H460) in BALB/c nude mice (Gagnadoux et al. 2005).
In dogs with primary lung cancer or lung metastases, inhaled paclitaxel and doxorubicin resulted in tumor shrinkage in 25% of the dogs, without producing adverse effects commonly seen with IV chemotherapy (Hershey et al. 1999). Aerosol administration of GEM to dogs who naturally developed lung metastases from osteosarcoma was well tolerated but did not produce any cures and did not prolong survival among the treated dogs (Rodriguez et al. 2010).
While earlier studies demonstrated the feasibility and relative safety of targeted direct local administration of chemotherapeutic agents to the lung, concerns about local toxicity could be reduced by employing formulations designed specifically for inhalation rather than the IV formulations of cisplatin and GEM that were employed in the previous investigations. Further investigations have been conducted to fulfill the need for formulations that are suitable for inhalation and do not cause local toxicity. For example, Feng and colleagues insufflated freeze-dried porous microspheres of PLGA loaded with doxorubicin and pacli- taxel into the lungs of C57BL/6J mice implanted with B16F10 melanoma cells (Feng et al. 2014). The combination of doxorubicin and paclitaxel had a synergistic effect in reducing the number of tumor lesions in the lungs of the mice without causing histological evidence of damage to healthy alveoli. Other novel formulations that could enhance the safety of inhaled chemotherapeutic agents while preserving their efficacy for treating lung cancers are under active investigation (Meenach et al. 2013, 2014).