Direct injection of liposome-encapsulated doxorubicin optimizes chemomyectomy in rabbit eyelid

Purpose. Doxorubicin chemomyectomy presently represents the only permanent, nonsurgical treatment for blepharospasm and hemifacial spasm. The major deterrent to an otherwise extremely effective treatment protocol is the development in patients of localized inflammation, discomfort, and skin injury over the injection site. As a potential alternative therapy, Doxil (Sequus, Menlo Park, CA), a liposome-encapsulated form of doxorubicin that displays tissue-selective therapeutic effects compared with free doxorubicin, was examined. These effects have been related to its increased retention in tissues and its sustained release over time. For the skin, Doxil is classified as an irritant rather than a vesicant. Methods. Rabbits received direct injections of 1, 2, or 3 mg Doxil alone or in sequence with other agents directly into the lower eyelids. The treated eyelids were examined daily for signs of skin injury. One month after the last injection, the rabbits were euthanatized, and their eyelids were examined histologically for the effect of Doxil on the orbicularis oculi muscle and the skin. Results. At equivalent milligram doses of free doxorubicin, Doxil spared the skin from injury. Doxil was only approximately 60% as effective in killing muscles as the same milligram dose of free doxorubicin. However, either two injections of Doxil spaced 2 months apart or preinjury of the lid with bupivacaine before a single dose of Doxil treatment resulted in increased muscle loss compared with a single dose of Doxil alone and was as effective as free doxorubicin. Higher doses of Doxil did not increase the desired myotoxic effect; apparently, the dose effect levels off at a maximum. Signs of skin injury were minimal; there were small or no adverse skin changes at the maximum effective myotoxic doses. Conclusions. Injection of Doxil resulted in significant reduction of skin injury compared with doxorubicin alone. Although single injections of Doxil were myotoxic, multiple exposure of the eyelid to the liposome-encapsulated form substantially improved myotoxicity while sparing the skin. Repeated doses of the liposome-encapsulated form of doxorubicin may be as clinically effective as free doxorubicin injections and may produce fewer unwanted side effects.