title: Octreotide-targeted liposomes loaded with CPT-11 enhanced cytotoxicity for the treatment of medullary thyroid carcinoma.
abstract: Medullary thyroid carcinoma (MTC) is a rare endocrine tumor that frequently metastasizes, but treatment with irinotecan (CPT-11) is limited because of side effects. MTC is known to overexpress the somatostatin receptor subtype 2 (SSTR2). Octreotide (Oct) is a somatostatin analogue that has a high binding affinity for SSTR and can be used as a tumor-targeting ligand. We prepared Oct-targeted liposomes loaded with CPT-11 using Oct-poly (ethylene glycol) (PEG)-lipid and evaluated Oct-mediated association and cytotoxicity of the liposomes with an MTC cell line TT. The association of higher concentrations of modified Oct-targeted liposomes with TT cells was significantly higher than PEGylated liposomes and was significantly inhibited by empty Oct-targeted liposomes but not by free Oct. With exposure for 96 h, the cytotoxicity of Oct-targeted liposomal CPT-11 (IC50: 1.05 ± 0.47 μM) was higher than free CPT-11 (IC50: 3.76 ± 0.61 μM) or PEGylated liposomal CPT-11 (IC50: 3.05 ± 0.28 μM). In addition, empty Oct-targeted liposomes showed significantly higher cytotoxicity than empty nontargeted liposomes at a concentration where free Oct did not show cytotoxicity, suggesting that Oct as a ligand showed cytotoxicity. Moreover, Oct-targeted liposomal CPT-11 led to significantly higher antitumor activity and prolonged the survival time compared with nontargeted liposomal and free CPT-11 at a one-third dose and lower administration times with free CPT-11. These findings indicated that Oct-targeted liposomes loaded with CPT-11 may offer considerable potential for MTC chemotherapy because cytotoxicity of both CPT-11 and Oct was enhanced by effective cellular uptake via SSTR2.
authors.affiliation: Institute of Medicinal Chemistry, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Iwase
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Maitani
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018278:Carcinoma, Neuroendocrine; D049109:Cell Proliferation / Q000187:drug effects; D004337:Drug Carriers; D005260:Female; D005434:Flow Cytometry; D005765:Gastrointestinal Agents / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D008081:Liposomes; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D015282:Octreotide / Q000627:therapeutic use*; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D005765:Gastrointestinal Agents; D008081:Liposomes; D017481:Receptors, Somatostatin; D000077146:Irinotecan; C093733:somatostatin receptor 2; D015282:Octreotide; D002166:Camptothecin