期刊
JOURNAL OF NUCLEAR MEDICINE
卷 58, 期 9, 页码 1380-1385出版社
SOC NUCLEAR MEDICINE INC
DOI: 10.2967/jnumed.117.189993
关键词
brachytherapy; polyoxazoline; thermoresponsive polymer; radiotherapy
资金
- JSPS KAKENHI [16H06256, 26860991]
- Shimazu Science Foundation
- Takeda Science Foundation
- Innovative Techno-Hub for Integrated Medical Bio-imaging Project of the Special Coordination Funds for Promoting Science and Technology, from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan
- Grants-in-Aid for Scientific Research [26860991, 16H06256] Funding Source: KAKEN
Brachytherapy is a type of radiotherapy wherein titanium capsules containing therapeutic radioisotopes are implanted within tumor tissues, enabling high-dose radioirradiation to tumor tissues around the seeds. Although marked therapeutic effects have been demonstrated, brachytherapy needs a complicated implantation technique under general anesthesia and the seeds could migrate to other organs. The aim of this study was to establish a novel brachytherapy using biocompatible, injectable thermoresponsive polymers (polyoxazoline [POZ]) labeled with Y-90, which can self-aggregate above a specific transition temperature (Tt), resulting in long-term intratumoral retention of radioactivity and therapeutic effect. Therefore, we evaluated the tumor retention of radiolabeled POZ derivatives and their therapeutic effects. Methods: Using oxazoline derivatives with ethyl (Et), isopropyl (Isp), and propyl (Pr) side chains, we synthesized EtPOZ, IspPOZ, Isp-PrPOZ (heteropolymer), and PrPOZ and measured their characteristic Tts. The intratumoral retention of In-111-labeled POZ was evaluated until 7 d after injection in nude mice bearing PC-3 human prostate cancer. The intratumoral localization of In-111-labeled POZ derivatives was investigated by an autoradiographic study. Furthermore, a therapeutic study using Y-90-labeled Isp-PrPOZ was performed, and tumor growth and survival rate were evaluated. Results: The Tts of EtPOZ, IspPOZ, Isp-PrPOZ, and PrPOZ (similar to 20 kDa) were greater than 70 degrees C, 34 degrees C, 25 degrees C, and 19 degrees C, respectively. In the intratumoral injection study, Isp-PrPOZ and PrPOZ (2,000 mM) with Tts lower than tumor temperature (33.5 degrees C under anesthesia) showed a significantly higher retention of radioactivity at 1 d after injection (73.6% and 73.9%, respectively) than EtPOZ (5.6%) and Isp-POZ (15.8%). Even at low injected dose (100 mM), Isp-PrPOZ exhibited high retention (68.3% at 1 d). The high level of radioactivity of Isp-PrPOZ was retained in the tumor 7 d after injection (69.5%). The autoradiographic study demonstrated that the radioactivity of In-111-labeled Isp-PrPOZ and PrPOZ was localized in a small area. In the therapeutic study using Y-90-labeled Isp-PrPOZ, significant suppression of tumor growth and prolonged survival rate were achieved in an injection dose-dependent manner compared with that observed for the vehicle-injected group and nonradioactive Isp-PrPOZ-injected group. Conclusion: The injectable Y-90-labeled Isp-PrPOZ was retained for a prolonged period within tumor tissues via self-aggregation and exhibited marked therapeutic effect, suggesting its usefulness for brachytherapy.
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