1 © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com Improved Photodynamic Cancer Treatment by Folate- Conjugated Polymeric Micelles in a KB Xenografted Animal Model Wei-Jhe Syu, Hsiu-Ping Yu, Chia-Yen Hsu, Yeasudhasan Christu Rajan, Yuan-Hung Hsu, Yuan-Chia Chang, Wen-Yuan Hsieh, Chau-Hui Wang, and Ping-Shan Lai* DOI: 10.1002/smll.201102695 W.-J. Syu, H.-P. Yu, C.-Y. Hsu, Y. C. Rajan, Prof. P.-S. Lai Department of Chemistry National Chung Hsing University No. 250, Kuo-Kuang Road, Taichung 402, Taiwan E-mail: pslai@email.nchu.edu.tw Dr. Y.-H. Hsu, Dr. Y.-C. Chang, Dr. W.-Y. Hsieh, Dr. C.-H. Wang Biomedical Technology and Device Research Laboratories Industrial Technology Research Institute, No. 195, Section 4, Chung- Hsing Road, Chu Tung Township, Hsin Chu 310, Taiwan 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. Photodynamic Therapy 1. Introduction Photodynamic therapy (PDT) is a light-induced chemical reaction resulting in topical damage by reactive oxygen spe- cies following activation of a photosensitizer with a specific light source. PDT is currently used in the treatment of cancer and various nonmalignant conditions; [1] however, the primary clinical side effect of PDT is skin photosensitivity, which limits the clinical applications of this therapeutic technique. [2] Hydrophobic photosensitizers tend to aggregate in aqueous solution, thus resulting in less photoactivation and less 1 O 2 small 2012, DOI: 10.1002/smll.201102695