Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy.
Anti-angiogenic therapy is a potential chemotherapeutic strategy for the treatment of drug resistant cancers. However, a method for delivering such drugs to tumor endothelial cells remains to be a major impediment to the success of anti-angiogenesis therapy. We designed liposomes (LPs) with controlled diameter of around 300 nm, and modified them with a specific ligand and a cell penetrating peptide (CPP) (a dual-ligand LP) for targeting CD13-expressing neovasculature in a renal cell carcinoma (RCC). We modified the LPs with an NGR motif peptide on the top of poly(ethylene glycol) and tetra-arginine (R4) on the surface of the liposome membrane as a specific and CPP ligand, respectively. The large size prevented extravasation of the dual-ligand LP, which allowed it to associate with target vasculature. While a single modification with either the specific or CPP ligand showed no increase in targetability, the dual-ligand enhanced the amount of delivered liposomes after systemic administration to OS-RC-2 xenograft mice. The anti-tumor activity of a dual-ligand LP encapsulating doxorubicin was evaluated and the results were compared with Doxil, which is clinically used to target tumor cells. Even though Doxil showed no anti-tumor activity, the dual-ligand LP suppressed tumor growth because the disruption of tumor vessels was efficiently induced. The comparison showed that tumor endothelial cells (TECs) were more sensitive to doxorubicin by 2 orders than RCC tumor cells, and the disruption of tumor vessels was efficiently induced. Collectively, the dual-ligand LP is promising carrier for the treatment of drug resistant RCC via the disruption of TECs.
Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Hokkaido, Japan.
Kazuhiro
K
Takara
Hiroto
H
Hatakeyama
Golam
G
Kibria
Noritaka
N
Ohga
Kyoko
K
Hida
Hideyoshi
H
Harashima
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D018826:CD13 Antigens / Q000378:metabolism*; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000378:metabolism*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007668:Kidney / Q000098:blood supply / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000188:drug therapy; D008024:Ligands; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D010316:Particle Size
D000903:Antibiotics, Antineoplastic; D057846:Cell-Penetrating Peptides; D008024:Ligands; D008081:Liposomes; C526428:NGR peptide; D009842:Oligopeptides; D004317:Doxorubicin; D018826:CD13 Antigens