Enhanced antitumor efficacy of folate-linked liposomal doxorubicin with TGF-β type I receptor inhibitor.
Tumor cell targeting of drug carriers is a promising strategy and uses the attachment of various ligands to enhance the therapeutic potential of chemotherapy agents. Folic acid is a high-affinity ligand for folate receptor, which is a functional tumor-specific receptor. The transforming growth factor (TGF)-β type I receptor (TβR-I) inhibitor A-83-01 was expected to enhance the accumulation of nanocarriers in tumors by changing the microvascular environment. To enhance the therapeutic effect of folate-linked liposomal doxorubicin (F-SL), we co-administrated F-SL with A-83-01. Intraperitoneally injected A-83-01-induced alterations in the cancer-associated neovasculature were examined by magnetic resonance imaging (MRI) and histological analysis. The targeting efficacy of single intravenous injections of F-SL combined with A-83-01 was evaluated by measurement of the biodistribution and the antitumor effect in mice bearing murine lung carcinoma M109. A-83-01 temporarily changed the tumor vasculature around 3 h post injection. A-83-01 induced 1.7-fold higher drug accumulation of F-SL in the tumor than liposome alone at 24 h post injection. Moreover F-SL co-administrated with A-83-01 showed significantly greater antitumor activity than F-SL alone. This study shows that co-administration of TβR-I inhibitor will open a new strategy for the use of FR-targeting nanocarriers for cancer treatment.
Taniguchi
Yukimi
Y
Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan.
Kawano
Kumi
K
Minowa
Takuya
T
Sugino
Takashi
T
Shimojo
Yuki
Y
Maitani
Yoshie
Y
D000818:Animals; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004357:Drug Synergism; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D013859:Thiocarbamates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013882:Thiosemicarbazones; D014018:Tissue Distribution
C507011:A-83-01; D011720:Pyrazoles; D018125:Receptors, Transforming Growth Factor beta; D013859:Thiocarbamates; D013882:Thiosemicarbazones; D004317:Doxorubicin; D005492:Folic Acid; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I