DELIVERY OF INHALED ANTICANCER AGENTS

Aerosol Deposition

Inhalation therapy provides a method for regional administration of anticancer agents to treat lung cancer. Other solid tumors have been successfully controlled with regional administration of immunotherapy, chemotherapy, and genetic manipulation. Inhalational delivery is a noninvasive method to achieve high pulmonary concentrations of the delivered agent, with low systemic toxicity, potential to target therapy, and avoid hepatic metabolism of drugs. The ability to achieve high concentrations of chemotherapeutic agents within lung tumors may be a critical factor in reducing treatment failures as well as emergence of resistance to treatment (Minchinton and Tannock 2006). With this approach, tumors that have become refractory to systemic chemotherapy could respond to inhalation treatment (Hershey et al. 1999; Chou et al. 2013). The development of novel, local administration of anticancer agents may help to better target the tumors and potentially reduce the occurrence of adverse effects due to systemically administered treatments. Inhalation therapy, therefore, has the potential to become an effective and safe treatment for patients with lung cancer.

Aerosol particle size, inspiratory flow rate, tidal volume, and airway geometry are among the several factors that influence aerosol deposition in the lungs (Dolovich and Dhand 2011). The optimal site for inhaled drug deposition may vary depending on the site of the tumor. Aerosols with larger mass median aerodynamic diameter (MMAD) of 4-5 pm target centrally located lung tumors, whereas slow inhalation of aerosols containing drug particles of 1-3 pm in diameter increases the likelihood of drug deposition in peripheral airways and alveoli and is more appropriate for targeting peripheral tumors (e.g., adenocarcinoma and pulmonary metastasis). Airway obstruction by the tumor or the presence of associated obstructive lung disease could influence aerosol deposition patterns. Likewise, the high humidity environment in the lung could alter the particle size of some drugs and change their deposition. Other physical properties of the aerosol particles, such as pH, electrostatic charge, and osmolarity, also play a role in drug deposition (Eschenbacher et al. 1984).

After deposition drugs undergo dissolution and are transported across the epithelial membranes for absorption into the circulation. In the conducting airways, the mucociliary clearance mechanisms transport particulate matter up to the oropharynx, whereas in the alveoli, the principal mechanism of clearance is by alveolar macrophage phagocytosis. In patients with lung cancer, drugs depositing on the conducting airways in the vicinity of tumors may not be rapidly removed by mucociliary clearance because tumor cells lack functioning cilia, allowing the drug more opportunities to reach the tumor by direct local penetration. Moreover, drugs depositing on the airways are distributed to other regions of the lung via a rich plexus of bronchial capillaries that have pre- and postcapillary connections with the pulmonary circulation (Deffebach et al. 1987). Due to these communications between the bronchial and pulmonary circulations, drugs administered by inhalation could achieve adequate drug concentrations even within small tumors that are located in the lung parenchyma and lack direct communication with a major airway.

The chemical characteristics and biological effects of drugs strongly influence their efficacy as anticancer agents. In addition, tumor size influences drug penetration. Drugs show variable penetration into tumors; drugs such as 5-fluorouracil (5-FU), which bind macromolecules minimally, readily penetrate and are uniformly cytotoxic throughout the tumor. In contrast, penetration of other drugs, such as pacli- taxel, within tumors is influenced by tumor cellularity, density of the interstitium, and apoptotic activity of the drug. In normal tissues, the net outward flow of fluid from the blood vessels is balanced by reabsorption into the lymphatic circulation. The interstitial pressure within tumors may be higher because they lack functional lymphatics, and the elevated interstitial fluid pressure could limit the distribution of some inhaled anticancer agents within the tumor. Thus, inhalation has the potential to achieve higher drug concentrations in the vicinity of the tumor; however, several other factors have to be considered in determining the ability of these agents to eradicate cancer cells.

 
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