**4.1 Animal models for aerosol delivery in cancer**

#### **4.1.1 Animal model for assessing lung deposition**

The structure of the human nasal system is very different from that of all other animals except the non-human primates. The nasal anatomy of primates (human and non-human) is much simpler than that of the majority of animals (Gross et al., 1991.). Rodents cannot breathe through their mouths. Particles must be smaller than 3 µm if they are to reach the airways of rodents (Miller et al., 2000). One way to avoid nasal deposition is to introduce a catheter connected to a high pressure syringe into the trachea to deliver aerosols directly into the lungs. There are two types of tracheo-bronchial anatomy, dichotomous division and monopodial division (McBride et al. 1991). The human respiratory tract is considered to undergo dichotomous branching, while those of rats, mice and dogs are monopodial. This anatomical difference does not seem to influence aerosol deposition in the lungs, but further studies are needed to confirm this. The transition between bronchial airways and the alveolar region is gradual in humans; humans have respiratory bronchioles, while rodents do not (Tyler et al., 1993). Inhaled particles are cleared faster from the alveoli of rodents than from the alveoli of humans because rodents lack bronchioles. However, additional studies are required to determine whether this difference influences the deposition of aerosolised particles in the lungs (Phalen et al., 2008). Total aerosol deposition is better in nasal breathing humans than in oral breathing humans. Upper respiratory tract deposition is similar in nasal breathing humans and in dogs, hamsters, and rabbits. However, pulmonary deposition in nasal breathing humans is comparable to that of dogs and monkeys, but lower than in hamsters and rats. The peak particle size for pulmonary deposition is larger in humans than in dogs, guinea pigs, monkeys, and rats (Phalen et al., 2008)

The Airways: A Promising Route for the Pulmonary Delivery of Anticancer Agents 59

The concentrations in the lungs of anticancer drugs delivered by the pulmonary route are higher than the concentrations delivered by any other route. Cisplatin, one of the major drugs used to treat lung cancers, is administered systemically. Delivery of cisplatin *via* a catheter placed in right caudal lung lobe in dogs provided a concentration in the right caudal lobe that was 44 times higher than in other pulmonary lobes (Selting et al., 2008). The pulmonary delivery of other anticancer drugs that are clinically injected intravenously, but are unconventional for treating non small cell lung cancer, was also tested. The deposition of aerosolised liposomal camptothecin, a quinoline alkaloid, in the lungs was assessed in nude mice with colon, breast or lung tumour xenografts. The concentration of the encapsulated camptothecin in the lung was 100 times higher following airways administration than after intramuscular injection (Koshkina et al., 1999). Similarly, the concentration of aeorosolised 5- Fluorouracile (5-FU) in the lung tissue was 1000 times higher than in the serum of hamsters (Hitzman et al., 2006). High concentrations of 5-FU were detected in the trachea and bronchi of dogs after airways delivery, whereas a lower concentration was measured in the peripheral lung (Tatsumura et al., 1993). We have used near infrared imaging to analyze the distribution of cetuximab, an anti-EGFR antibody, in a xenograft model of lung tumour following systemic and pulmonary delivery, (Maillet et al., in press). The antibody accumulated rapidly and durably in the lungs (Figure 1), and the lung concentration was

**4.2 Pharmacokinetics of anticancer agents delivered** *via* **the airways in animals** 

higher following airways delivery (not shown) (Maillet et al., in press).

A B C D E

Fig. 1. Lung deposition of inhaled cetuximab at (A) 1h30 (B) 8h (C) 24h (D) 48h and (E) 72h.

Most studies have shown that the concentration of an anticancer drug in the bloodstream is lower after airways delivery than after systemic injection. For example, the concentration of cisplatin in the serum was 15.6 times lower after pulmonary administration than after intravenous (i.v.) injection (Selting et al., 2008). Gemcitabine was given to 3 baboons *via* the airways and its concentration in the blood was 25 times lower than after its systemic delivery (Gagnadoux et al., 2006). Dogs with spontaneous pulmonary metastases were given aerosolized paclitaxel and doxorubicin and the drug concentrations in the bloodstream were measured 1 minute later (Hershey et al., 1999). The serum concentrations were lower than when the drugs were delivered intravenously. However a pharmacokinetic analysis is

**4.2.1 Lung deposition** 

**4.2.2 Blood passage** 
