Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy

• Published in: Journal of controlled release 2012-08, Vol.162 (1), p.225-232
• Main Authors: Takara, Kazuhiro, Hatakeyama, Hiroto, Kibria, Golam, Ohga, Noritaka, Hida, Kyoko, Harashima, Hideyoshi
• Format: Article
• Language: English
• Subjects: Animals; Anti-angiogenesis; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - pharmacology; Antibiotics, Antineoplastic - therapeutic use; anticarcinogenic activity; Biological and medical sciences; carcinoma; CD13 Antigens - metabolism; Cell Line, Tumor; Cell-Penetrating Peptides - chemistry; Cell-Penetrating Peptides - metabolism; doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug delivery; Drug Delivery Systems; drug resistance; Drug Resistance, Neoplasm; Drug resistant tumor; drug therapy; Dual ligand; encapsulation; endothelial cells; ethylene glycol; General pharmacology; Humans; Kidney - blood supply; Kidney - cytology; Kidney - drug effects; Kidney - pathology; Kidney Neoplasms - blood supply; Kidney Neoplasms - drug therapy; Ligands; Liposomes - chemistry; Liposomes - metabolism; Male; Medical sciences; Mice; Mice, Inbred BALB C; neoplasm cells; Oligopeptides - chemistry; Oligopeptides - metabolism; Particle Size; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Tumor endothelial cells
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2012.06.019

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 300nm, 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. [Display omitted]