Liposome -mediated delivery of all-{\it trans\/}-retinoic acid

Because of its antiproliferative and differentiation-inducing properties, all-trans-retinoic acid (ATRA) has been used as a chemopreventive and therapeutic agent, for treatment various cancers including squamous cell carcinomas (SCCs). Long-term treatment with ATRA is associated with toxic effects in patients leading to acute or chronic hypervitaminosis syndrome. Moreover, prolonged treatment with oral ATRA leads to acquired resistance to the differentiation-inducing effects of the drug. This resistance is attributed to the induction of cytochrome P-450-dependent catabolic enzymes that lead to accelerated ATRA metabolism and decline in circulating levels. Most of these problems could be circumvented by incorporating ATRA in liposomes (L-ATRA) which results in sustained drug release, decrease in drug-associated toxicity, and protection of the drug from metabolism in the host. Liposomes also function as a solubilization matrix enabling lipophilic drugs like ATRA to be aerosolized and delivered directly to target areas in the aerodigestive tract and lungs. Of the 14 formulations tested, the positively-charged liposome, DPPC:SA (9:1, w/w) was found to be most effective in interacting with SCC cell lines. This, L-ATRA formulation was stable in the presence of serum proteins and buffered the toxic effects of the drug against several normal and malignant cell lines. The positive charge attributed by the presence of SA was critical for increased uptake and retention of L-ATRA by SCC cell lines and tumor spheroids. L-ATRA was highly effective in mediating differentiation in normal and transformed epithelial cells. Moreover, liposomal incorporation significantly reduced the rate of ATRA metabolism by cells and isolated liver microsomes. In vivo studies revealed that aerosol delivery is an effective way of administering L-ATRA, in terms of its safety and retention by lung tissue. The drug so delivered, is biologically active and had no toxic effects in mice. From these results, we conclude that liposome-incorporation is an excellent way of delivering ATRA to target tissues. The results obtained may have important clinical implications in treating patients with SCCs of the aerodigestive tract. ^