Aerosol delivery of liposomal all-trans-retinoic acid to the lungs.

PURPOSE

To optimize the delivery of all-trans-retinoic acid (ATRA) to lung tissue, we determined the potential of vehiculating the drug in liposomes (L-ATRA) and delivering it via aerosol. Liposomes may provide a means to prevent local irritation of lung tissue and reduce pulmonary toxicity, prolong therapeutic levels and generate high drug concentrations at the tumor sites. Cumulatively, this would result in reduced systemic toxicity and enhanced drug efficacy.

METHODS

Previous studies have shown that liposomes can serve as excellent carriers for otherwise poorly soluble ATRA. Delivery of ATRA to the lung tissue of mice was accomplished by nebulization of L-ATRA. The liposomes in the aerosol were relatively uniform (309 +/- 138 nm), stable, and retained the drug well.

RESULTS

The drug was effectively delivered at high concentrations (10 +/- 2 microg/g of tissue) to the lungs of mice and was retained for at least up to 96 h after a single exposure to L-ATRA aerosol. No appreciable levels of ATRA were detected in the blood or the liver of treated mice. The aerosol-delivered ATRA was biologically active as demonstrated by its ability to induce the expression of tissue-type transglutaminase.

CONCLUSION

Aerosol delivery of L-ATRA offers an effective way to deliver high levels of ATRA to the lung without apparent pulmonary toxic effects.