Enhancement of radiotherapeutic effectiveness by temperature-sensitive liposomal 1-methylxanthine.
Most of methylxanthine derivatives including caffeine have been known to radiosensitize cancer cells, but the obstacles such as toxicity, request of high dose and poor solubility hinder their preclinical evaluations and clinical applications. In this study, we evaluated the efficacy of 1-methylxanthine (1-MTX), a caffeine metabolite as a radiosensitizer and the in vivo effectiveness of the temperature-sensitive liposomal 1-methylxanthine (tsl-MTX) in combination with ionizing radiation and regional hyperthermia. In human colorectal and lung cancer cells, treatment of 1-MTX sensitized cells to ionizing radiation. To evaluate the in vivo capability of 1-MTX to radiosensitize tumors, we developed temperature-sensitive liposomal 1-MTX using DPPC:DMPC:DSPC (4:1:1 molar ratio) with intention of overcoming lethal toxicity of 1-MTX and controlling drug-release. The particle size of the liposomes was approximately 200 nm in diameter. The release of 1-MTX from the liposomes was responding to increase of temperature. In xenograft tumor-bearing mice, the tsl-MTX administered using the i.p. route showed delay of tumor growth. Importantly, tsl-MTX in combination with radiation and regional hyperthermia exhibited marked delay of tumor growth, suggesting that 1-MTX effectively enhanced radiation-induced suppression of tumor growth. In conclusion, tsl-MTX has highly efficacious anticancer competence in vivo, enhancing radiotherapeutic effectiveness, and feasibility for further clinical applications.
Jeong
Seong-Yun
SY
Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Republic of Korea.
Yi
So Lyoung
SL
Lim
Sun-Kyung
SK
Park
Sung-Jin
SJ
Jung
Joohee
J
Woo
Ha Na
HN
Song
Si Yeol
SY
Kim
Jin-Seok
JS
Lee
Jung Shin
JS
Lee
Jin Seong
JS
Park
Heon Joo
HJ
Choi
Eun Kyung
EK
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011838:Radiation-Sensitizing Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013696:Temperature; D014970:Xanthines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D008081:Liposomes; D011838:Radiation-Sensitizing Agents; D014970:Xanthines; C053085:1-methylxanthine