药学学报, 2019, 54(5): 927-936
引用本文:
罗雷, 刘江波, 尹珍, 周旭阳, 徐凡舒, 罗永煌. 生物可降解胶束为载体的双光子光动力疗法抗小鼠乳腺癌实验研究[J]. 药学学报, 2019, 54(5): 927-936.
LUO Lei, LIU Jiang-bo, YIN Zhen, ZHOU Xu-yang, XU Fan-shu, LUO Yong-huang. Biodegradable micelles for two-photon photodynamic therapy in a mouse model of breast cancer[J]. Acta Pharmaceutica Sinica, 2019, 54(5): 927-936.

生物可降解胶束为载体的双光子光动力疗法抗小鼠乳腺癌实验研究
罗雷, 刘江波, 尹珍, 周旭阳, 徐凡舒, 罗永煌
西南大学药学院, 重庆 400716
摘要:
光动力疗法(photodynamic therapy,PDT)是利用光和光敏剂高效治疗肿瘤的方法。但多数光敏剂在体内分布的选择性差、难溶于水以及仅能被穿透力较弱的光线激发而限制了疗效。本文利用生物可降解胶束甲氧基聚乙二醇-b-聚D,L-丙交酯[methoxy poly(ethylene glycol)-polylactide copolymer,mPEG-PDLLA]作为药物载体,增加光敏剂的溶解度,便于静脉注射,并通过尺寸效应提高药物在肿瘤部位的分布,同时在此载体中包埋新型强双光子吸收化合物(two-photon absorption compound,LTPA),作为近红外激光的转换器以间接激发光敏剂焦脱镁叶绿酸a(pyropheophorbide a,PPa),旨在增强对生物组织的穿透力,高效杀死肿瘤细胞,实现双光子光动力疗法。结果表明,激光粒度仪测得该胶束的粒径约为55 nm,在电镜下呈形态规则的球形,粒径均一,包埋的双光子化合物和光敏剂可在酸性或中性pH值下从胶束中同步释放,且在808 nm近红外激光照射后,检测到单线态氧生成;在细胞实验中,4T1小鼠乳腺癌细胞在双光子光动力疗法(TP-PDT)的作用下,存活率受到明显抑制,且通过Annexin-V/FITC标记后发现大量细胞被诱导凋亡/坏死;载药胶束在小鼠肿瘤模型上(动物实验符合中国实验动物护理和使用准则,并经西南大学药学院实验动物伦理委员会批准)具有一定的靶向蓄积作用,TP-PDT对肿瘤生长具有较明显的抑制效果。综上,基于胶束为载体的TP-PDT是改进现有光动力疗法弊端的新尝试,在抗肿瘤的应用上具有良好的探索前景。
关键词:    胶束      单线态氧      双光子吸收      光动力疗法      乳腺癌     
Biodegradable micelles for two-photon photodynamic therapy in a mouse model of breast cancer
LUO Lei, LIU Jiang-bo, YIN Zhen, ZHOU Xu-yang, XU Fan-shu, LUO Yong-huang
College of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China
Abstract:
Photodynamic therapy (PDT) is one of the new approaches for cancer treatment with high efficacy. However, applications of current photosensitizers are restricted to skin and superficial tumor due to poor in vivo targeting ability, poor water solubility and short wavelength excitement, which limits penetration therefore thera peutic depth. Here, a biodegradable polymeric micelle, methoxy poly(ethylene glycol)-polylactide copolymer (mPEG-PDLLA), is employed as drug delivery system to co-encapsulate strong two-photon absorption compound (LTPA) and photosensitizers. This delivery system is designed to target tumor passively, resulting in near infrared light with an approximately 808 nm wavelength becoming able to indirectly excite photosensitizers through fluores cence resonance energy transfer. Tumor cells and microvessels could be damaged by the generated singlet oxygen. The average size of drug loaded micelles was approximately 55 nm and showed a spherical shape. Both com pounds could be released simultaneously from micelles under either weak acid and neutral pH conditions. Reactive oxygen species was produced intracellularly during two-photon PDT process and induced cell apoptosis/necrosis, which was quantified by Annexin-V/FITC assays. Time-dependent ex vivo organ distribution and in vivo anticancer efficacy results suggested that the drug carriers could accumulate in tumors and suppress tumor growth by twophoton PDT. All animals experiments were performed in line with national regulations and approved by the Animal Experiments Ethical Committee of College of Pharmaceutical Sciences, Southwest University. In summary, we have employed two-photon PDT for breast cancer treatment successfully in a mouse model and have demonstrated the significance of delivery system in such therapeutics.
Key words:    micelle    singlet oxygen    two-photon absorption    photodynamic therapy    breast cancer   
收稿日期: 2019-01-10
DOI: 10.16438/j.0513-4870.2019-0037
基金项目: 国家自然科学基金资助项目(81503009).
通讯作者: 罗雷,Tel/Fax:86-23-68251225,E-mail:drluolei@swu.edu.cn
Email: drluolei@swu.edu.cn
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