title: Liposomal Coencapsulation of Doxorubicin with Listeriolysin O Increases Potency via Subcellular Targeting.
abstract: Liposomal doxorubicin is a clinically important drug formulation indicated for the treatment of several different forms of cancer. For doxorubicin to exert a therapeutic effect, it must gain access to the nucleus. However, a large proportion of the liposomal doxorubicin dose fails to work because it is sequestered within endolysosomal organelles following endocytosis of the liposomes due to the phenomenon of ion trapping. Listeriolysin O (LLO) is a pore-forming protein that can provide a mechanism for endosomal escape. The present study demonstrates that liposomal coencapsulation of doxorubicin with LLO enables a significantly larger percentage of the dose to colocalize with the nucleus compared to liposomes containing doxorubicin alone. The change in intracellular distribution resulted in a significantly more potent formulation of liposomal doxorubicin as demonstrated in both the ovarian carcinoma cell line A2780 and its doxorubicin-resistant derivative A2780ADR.
authors.affiliation: Department of Pharmaceutical Sciences, ‡Center for Inflammation, Infectious Disease and Immunity, §Department of Biomedical Sciences, and ∥Department of Biological Sciences, East Tennessee State University , Johnson City, Tennessee 37604, United States.
authors.forename: Zachary F
authors.initials: ZF
authors.lastname: Walls
authors.affiliation: Department of Pharmaceutical Sciences, ‡Center for Inflammation, Infectious Disease and Immunity, §Department of Biomedical Sciences, and ∥Department of Biological Sciences, East Tennessee State University , Johnson City, Tennessee 37604, United States.
authors.forename: Henry
authors.initials: H
authors.lastname: Gong
authors.affiliation: Department of Pharmaceutical Sciences, ‡Center for Inflammation, Infectious Disease and Immunity, §Department of Biomedical Sciences, and ∥Department of Biological Sciences, East Tennessee State University , Johnson City, Tennessee 37604, United States.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Wilson
mesh_terms: D001427:Bacterial Toxins / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004359:Drug Therapy, Combination; D005260:Female; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000494:pharmacology*; D006460:Hemolysin Proteins / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D013347:Subcellular Fractions; D014407:Tumor Cells, Cultured
chemical_list: D001427:Bacterial Toxins; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; C038705:hlyA protein, Listeria monocytogenes
keywords: Cancer; drug-resistance; endosomal escape; pH-sensitive