title: Bubble liposomes and ultrasound enhance the antitumor effects of AG73 liposomes encapsulating antitumor agents.
abstract: Encapsulating anticancer drugs in liposomes improves their therapeutic window by enhancing antitumor efficacy and reducing side effects. To devise more effective liposomal formulations for antitumor therapy, many research groups have tried to develop tumor-targeting liposomes with enhanced drug release. Previously, we developed doxorubicin (Dox)-encapsulated AG73 peptide-modified liposomes (AG73-Dox), which targeted cancer and endothelial cells, and ultrasound (US) imaging gas-entrapping liposomes, called "Bubble liposomes" (BLs). In this study, to enhance the antitumor effect of AG73-Dox, we combined AG73-Dox with BLs and US. First, to determine whether the addition of BLs and application of US could enhance the cytotoxicity of AG73-Dox, we evaluated the cytotoxicity of the combination of AG73-Dox with BLs and US. BLs and US enhanced cytotoxicity of AG73-Dox more than they enhanced nontargeted Dox-encapsulated liposomes. Next, we examined the intracellular behavior of Dox after treatment with BLs and US. The combination of AG73-Dox with BLs and US did not enhance cellular uptake of Dox, but it did promote drug release in the cytoplasm. To further elucidate the release of Dox in the cytoplasm, we blocked cellular uptake via endosomes at a low temperature. As a result, BLs and US did not have an enhanced drug-release effect until AG73-Dox was taken up into cells. Thus, the combination of AG73-Dox with BLs and US may be useful for cancer therapy as a dual-function drug delivery system with targeted and controlled release.
authors.affiliation: Department of Drug Delivery and Molecular Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Hamano
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Negishi
authors.forename: Daiki
authors.initials: D
authors.lastname: Omata
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Maya
authors.initials: M
authors.lastname: Manandhar
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Maruyama
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Nomizu
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Aramaki
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D002460:Cell Line; D005434:Flow Cytometry; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D018613:Microscopy, Confocal; D008954:Models, Biological; D014465:Ultrasonics
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes