Targeting of Liposomes to Solid Tumors: The Case of Sterically Stabilized Anti-Her2 Immunoliposomes

Abstract

Novel therapies for cancer call for a carrier capable of intracellular delivery of systemically administered drugs to cancer cells in solid tumors. Such carrier, sterically stabilized immunoliposomes specific to the cells expressing HER2 protooncogene (anti-HER2 SSL), was designed by conjugating Fab' fragments of a recombinant humanized anti-HER2 MAb to the distal termini of poly(ethylene glycol) chains on the surface of unilamellar liposomes (size 90-100 nm) of phosphatidylcholine, cholesterol, and poly(ethylene glycol)-derivatized phosphatidylethanolamine. Anti-HER2 SSL avidly and specifically bound to cultured HER2-overexpressing cancer cells (8,000-23,000 vesicles per cell) and became endocytosed (ke=0.022–0.033 min.-1) via the coated pit pathway. Anti-HER2 SSL showed prolonged circulation lifetime in rats (blood MRT approx. 24 hours) and significantly increased antitumor activity of encapsulated doxorubicin against HER2-overexpressing human breast cancer xenografts in nude mice. Although the accumulation of anti-HER2 SSL in HER2-overexpressing tumor xenografts was not increased over that of non-targeted SSL, microscopic examination revealed abundance of anti-HER2 SSL in the interstitial spaces, as well as within the cytoplasm of cancer cells, while identical liposomes lacking anti-HER2 Fab' were located predominantly within tumor-resident macrophages. Anti-HER2 SSL, a targeted vehicle capable of in vivo intracellular delivery of substances to HER2-overexpressing solid cancers, enhances the potential for tumor targeting and opens new avenues for better treatment of cancer.