Efficient drug delivery of Paclitaxel glycoside: a novel solubility gradient encapsulation into liposomes coupled with immunoliposomes preparation

• Published in: PloS one Vol. 9; no. 9; p. e107976
• Main Authors: Shigehiro, Tsukasa, Kasai, Tomonari, Murakami, Masaharu, Sekhar, Sreeja C, Tominaga, Yuki, Okada, Masashi, Kudoh, Takayuki, Mizutani, Akifumi, Murakami, Hiroshi, Salomon, David S, Mikuni, Katsuhiko, Mandai, Tadakatsu, Hamada, Hiroki, Seno, Masaharu
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.09.2014; Public Library of Science (PLoS)
• Subjects: Animals; Biocompatibility; Biomedical materials; Biotechnology; Breast cancer; Cancer; Cancer therapies; Cell cycle; Cytotoxicity; Drug Carriers; Drug delivery; Drug delivery systems; Encapsulation; Epidermal growth factor; ErbB-2 protein; Ethanol; Ethylene glycol; Female; Glycerol; Glycoproteins; Glycosides; Glycosides - administration & dosage; HT29 Cells; Humans; Hydrophobicity; Kinases; Lethal dose; Ligands; Lipids; Liposomes; Medicine and Health Sciences; Mice; Mice, Inbred BALB C; Monoclonal antibodies; Nanoparticles; Paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - chemistry; Polyethylene glycol; Polymerization; Science; Solubility; Targeted cancer therapy; Toxicity; Trastuzumab; Tubulin; Tumors; Xenografts; United States > US; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0107976

Although the encapsulation of paclitaxel into liposomes has been extensively studied, its significant hydrophobic and uncharged character has generated substantial difficulties concerning its efficient encapsulation into the inner water core of liposomes. We found that a more hydrophilic paclitaxel molecule, 7-glucosyloxyacetylpaclitaxel, retained tubulin polymerization stabilization activity. The hydrophilic nature of 7-glucosyloxyacetylpaclitaxel allowed its efficient encapsulation into the inner water core of liposomes, which was successfully accomplished using a remote loading method with a solubility gradient between 40% ethylene glycol and Cremophor EL/ethanol in PBS. Trastuzumab was then conjugated onto the surface of liposomes as immunoliposomes to selectively target human epidermal growth factor receptor-2 (HER2)-overexpressing cancer cells. In vitro cytotoxicity assays revealed that the immunoliposomes enhanced the toxicity of 7-glucosyloxyacetylpaclitaxel in HER2-overexpressing cancer cells and showed more rapid suppression of cell growth. The immunoliposomes strongly inhibited the tumor growth of HT-29 cells xenografted in nude mice. Notably, mice survived when treated with the immunoliposomes formulation, even when administered at a lethal dose of 7-glucosyloxyacetylpaclitaxel in vivo. This data successfully demonstrates immunoliposomes as a promising candidate for the efficient delivery of paclitaxel glycoside.