Development of a novel drug delivery system consisting of an antitumor agent tocopheryl succinate.
We have developed a novel drug delivery system (DDS) using an antitumor agent, α-tocopheryl succinate (TS). TS has attracted attention as a unique anti-cancer drug for its ability to induce apoptosis in various cancer cells. Furthermore, TS itself readily forms nanovesicles (TS-NVs) and is a prospective tool for use as an antitumor DDS. However, TS-NVs are unstable for encapsulating drugs and passive targeting delivery to tumor tissue via enhanced permeation and retention effect. Therefore, to improve the stability of vesicles, we developed a novel nanovesicle consisting of TS and egg phosphatidylcholine (TS-EPC-NVs). The stability of vesicles of TS-EPC-NVs was significantly higher than that of TS-NVs. As a result, the in vivo antitumor activity of TS-EPC-NVs was more potent than that of TS-NVs. The enhanced antitumor activity of TS-EPC-NVs was found to be due to its effective intratumoral distribution. Moreover, the in vitro anticancer efficiency of TS-EPC-NVs increased seven-fold. We suggest that the improvement is due to homogenous cellular uptake and enhanced cytosolic delivery of the nanovesicles via alteration of intracellular trafficking. Furthermore, TS-EPC-NVs encapsulating siRNA showed significant knockdown efficiency. In summary, TS-EPC-NVs represent a novel and attractive drug delivery system. The system shows antitumor activity of the encapsulated drug and the carrier itself.
Department of Biophysical Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
Susumu
S
Hama
Satoru
S
Utsumi
Yuki
Y
Fukuda
Kayoko
K
Nakayama
Yuriko
Y
Okamura
Hiroyuki
H
Tsuchiya
Kenji
K
Fukuzawa
Hedeyoshi
H
Harashima
Kentaro
K
Kogure
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D004912:Erythrocytes / Q000473:pathology; D006461:Hemolysis / Q000187:drug effects; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008812:Mice, Hairless; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry; D010713:Phosphatidylcholines / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D024505:Tocopherols / Q000008:administration & dosage* / Q000737:chemistry; D047368:Tumor Burden / Q000187:drug effects
D000970:Antineoplastic Agents; D004337:Drug Carriers; D010713:Phosphatidylcholines; D053148:Caspase 3; D053179:Caspase 7; D024505:Tocopherols