In vivo assessment of temozolomide local delivery for lung cancer inhalation therapy

• Published in: European journal of pharmaceutical sciences 2010-03, Vol.39 (5), p.402-411
• Main Authors: Wauthoz, Nathalie, Deleuze, Philippe, Hecq, Julien, Roland, Isabelle, Saussez, Sven, Adanja, Ivan, Debeir, Olivier, Decaestecker, Christine, Mathieu, Véronique, Kiss, Robert, Amighi, Karim
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Aerosol therapy; Animals; Antineoplastic Agents - administration & dosage; Biological and medical sciences; Cell Line, Tumor; Chromatography, High Pressure Liquid; Dacarbazine - administration & dosage; Dacarbazine - analogs & derivatives; Female; Fluorescent Dyes; Fluorescent microparticles; General pharmacology; Lung Neoplasms - drug therapy; Lung Neoplasms - secondary; Lung pseudo-metastases; Medical sciences; Melanoma, Experimental - pathology; Mice; Mouse B16F10 melanoma; NSCLC; Particle Size; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Reproducibility of Results; Temozolomide
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2010.01.010

The aim of this study was to compare the efficacy of local drug delivery by inhalation to intravenous delivery in a B16F10 melanoma metastatic lung model. Temozolomide was formulated as a suspension, which was elaborated and evaluated in terms of particle size, shape and agglomeration. An endotracheal administration device was used to aerosolise the suspension. This mode of delivery was evaluated at different temozolomide concentrations and was optimized for the uniformity of delivered dose, the droplet size distribution and the distribution of droplets in vivo. Of the particles in the stabilised suspension, 79% were compatible with the human respirable size range, and this formulation retained 100% in vitro anticancer activity as compared to temozolomide alone in three distinct cancer cell lines. The pulmonary delivery device provided good reproducibility in terms of both the dose delivered and the droplet size distribution. Most of the lung tissues that were exposed to aerosol droplets contained the particles, as revealed by fluorescent microscopy techniques. The global in vivo antitumour activity of the inhaled temozolomide provided a median survival period similar to that for intravenous temozolomide delivery, and three out of 27 mice (11%) survived with almost complete eradication of the lung tumours. The present study thus shows that inhalation of a simple liquid formulation is well tolerated and active against a very biologically aggressive mouse melanoma pulmonary pseudo-metastatic model. This inhalation delivery could be used to deliver other types of anticancer drugs.