Department of Chemistry, National Chung Hsing University, No. 250 Kuo-Kuang Road, Taichung, Taiwan.
Small. 2012 Jul 9;8(13):2060-9. doi: 10.1002/smll.201102695. Epub 2012 Apr 17.
Photodynamic therapy (PDT) is a light-induced chemical reaction that produces localized tissue damage for the treatment of cancers and various nonmalignant conditions. In the clinic, patients treated with PDT should be kept away from direct sunlight or strong indoor lighting to avoid skin phototoxicity. In a previous study, it was demonstrated that the skin phototoxicity of meta-tetra(hydroxyphenyl)chlorin (m-THPC), a photosensitizer used in the clinic, can be significantly reduced after micellar encapsulation; however, no improvement in antitumor efficacy was observed. In this work, a folate-conjugated polymeric m-THPC delivery system is developed for improving tumor targeting of the photosensitizer, preventing photodamage to the healthy tissue, and increasing the effectiveness of the photosensitizers. The results demonstrate that folate-conjugated m-THPC-loaded micelles with particle sizes around 100 nm are taken up and accumulated by folate receptor-overexpressed KB cells in vitro and in vivo, and their PDT has no significant adverse effects on the body weight of mice. After an extended delivery time, a single dose of folate-conjugated m-THPC-loaded micelles has higher antitumor effects (tumor growth inhibition = 92%) through inhibition of cell proliferation and reduction of vessel density than free m-THPC or m-THPC-loaded micelles at an equivalent m-THPC concentration of 0.3 mg kg(-1) after irradiation. Furthermore, folate-conjugated m-THPC-loaded micelles at only 0.2 mg kg(-1) m-THPC have a similar antitumor efficacy to m-THPC or m-THPC-loaded micelles with the m-THPC concentration at 0.3 mg kg(-1) , which indicates that the folate conjugation on the micellar photosensitizer apparently reduces the requirement of m-THPC for PDT. Thus, folate-conjugated m-THPC-loaded micelles with improved selectivity via folate-folate receptor interactions have the potential to reduce, not only the skin photosensitivity, but also the drug dose requirement for clinical PDT.
光动力疗法（PDT）是一种光诱导的化学反应，可产生局部组织损伤，用于治疗癌症和各种非恶性疾病。在临床上，接受 PDT 治疗的患者应避免直接阳光或强烈的室内照明，以避免皮肤光毒性。在以前的研究中，已经证明，用于临床的光敏剂间四（对羟基苯基）氯（m-THPC）经胶束包封后，皮肤光毒性可显著降低；然而，抗肿瘤疗效未见改善。在这项工作中，开发了一种叶酸偶联的聚合物 m-THPC 递药系统，用于提高光敏剂的肿瘤靶向性、防止健康组织的光损伤，并增加光敏剂的有效性。结果表明，粒径约为 100nm 的叶酸偶联 m-THPC 载药胶束在体外和体内被叶酸受体过表达的 KB 细胞摄取和积累，其 PDT 对小鼠体重没有明显的不良影响。在延长的递送时间后，与游离 m-THPC 或 m-THPC 载药胶束相比，在相同的 m-THPC 浓度（0.3mgkg-1）下，单次给予叶酸偶联 m-THPC 载药胶束通过抑制细胞增殖和减少血管密度具有更高的抗肿瘤效果（肿瘤生长抑制率=92%）。此外，仅以 0.2mgkg-1m-THPC 的叶酸偶联 m-THPC 载药胶束具有与 m-THPC 浓度为 0.3mgkg-1 的 m-THPC 或 m-THPC 载药胶束相似的抗肿瘤疗效，这表明胶束光敏剂上的叶酸偶联明显降低了 PDT 对 m-THPC 的要求。因此，通过叶酸-叶酸受体相互作用提高选择性的叶酸偶联 m-THPC 载药胶束有可能降低皮肤光敏性，同时也降低临床 PDT 的药物剂量需求。
