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

Abstract

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.

Temozolomide-Based Dry Powder Formulations for Lung Tumor-Related Inhalation Treatment

“…In our previous in vivo experimental study relying on the use of a mouse melanoma pseudometastatic lung model (24), we obtained the same efficacy in terms of median survival period when comparing TMZ administered through inhalation to TMZ administered intravenously (23). In addition, the local inhaled therapy resulted in long-term mouse survivors who showed an almost complete eradication of lung tumors (23). Considering a potential transposition of such a treatment in humans, if no reduction in the dose is achieved, a dose of 320 mg for an adult of 60 kg must be delivered by inhalation.…”

“…In a previous study, we showed that to obtain an equivalent antitumor efficacy by inhalation, we had to deliver the same TMZ dose at a similar frequency to those used for the intravenous route (23). These high doses and frequency could be explained by fast dissolution and elimination of the liquid suspension containing the TMZ particles from the lung.…”

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

“…(Wauthoz et al, 2010). The treatment seemed to be very well tolerated because the maximum tolerated dose was not reached.…”

Antitumor activity of intratracheal inhalation of temozolomide (TMZ) loaded into gold nanoparticles and/or liposomes against urethane-induced lung cancer in BALB/c mice

“…The ideal particles were produced upon addition of 25 mL of AuCl 4 (0.001 M) to trisodium citrate (2.5 mL, 0.04 M). TMZ (6 mg) was dissolved in 1 ml of phosphate buffer solution (pH 7.4), then 500 mL of the formed solution was mixed with 500 mL of gold solution and agitated by ultrasonication for one hour to obtain TGNPs and locally administered by microsprayer in concentration (0.3 mg/ 100 mL/puff) (Wauthoz et al, 2010).…”