Dendrimer Generation Effects on Photodynamic Efficacy of Dendrimer Porphyrins and Dendrimer-Loaded Supramolecular Nanocarriers Yuan Li, † Woo-Dong Jang,* ,‡ Nobuhiro Nishiyama, § Akihiro Kishimura, †,+,@ Satoko Kawauchi, | Yuji Morimoto, | Sayaka Miake, ⊥ Takashi Yamashita, ⊥ Makoto Kikuchi, | Takuzo Aida, #,@ and Kazunori Kataoka* ,†,§,+,@ Department of Materials Engineering, Graduate School of Engineering, The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan, Department of Chemistry, College of Science, Yonsei UniVersity, 134 Sinchondong, Seodaemun-gu, Seoul 120-749, Korea, Center for Disease Biology and IntegratiVe Medicine, Graduate School of Medicine, The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, Department of Medical Engineering, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan, Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo UniVersity of Science, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan, Department of Chemistry and Biotechnology, Graduate School of Engineering, The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan, Core Research for EVolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), and Center for NanoBio Integration, The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan ReceiVed May 29, 2007. ReVised Manuscript ReceiVed July 17, 2007 A series of poly(benzyl ether) dendrimer porphyrins (DPs) (Gn ) n-generation dendrimer, n ) 1-3) was examined as potential photosensitizers for photodynamic therapy (PDT). Polyion complexes (PICs) between the DPs and poly(ethylene glycol)-block-poly(L-lysine) (PEG-b-PLL) were formed via an electrostatic interaction between the positively charged poly(L-lysine) (PLL) segment and negatively charged periphery of the DPs. Dynamic light scattering (DLS) measurements and transmission electron microscopy (TEM) showed that G3 formed a core-shell-type nanocarrier micelle, whereas G1 and G2 formed irregular-shaped nanoparticles with a relatively high polydispersity. The photophysical properties of the DP-loaded PIC nanocarriers strongly depend on the generation of the DPs. In the case of G1 and G2, their fluorescence lifetime and oxygen consumption ability were significantly reduced by the formation of the PIC nanocarriers, whereas the G3-loaded PIC nanocarrier exhibited almost comparable fluorescence lifetimes and oxygen consumption abilities to the free G3. The incorporation of DPs into PIC nanocarriers resulted in an appreciable increase in the cellular uptake, yet inversely correlated with the generation. Alternatively, the photocytotoxicity of the DPs within the nanocarriers increased with an increase in the generation despite a decrease in the cellular uptake. By correlating the effects of the uptake amount with the photocytotoxicity, the PIC nanocarriers showed remarkable enhancement of the PDT efficacy dependent on the generation of DPs. Introduction Dendrimers with predictable three-dimensional architec- tures are currently undergoing fast growth in various ap- plications. This is due in part to the variety of applications being pursued for dendrimers. 1,2 In particular, application of dendrimers to biomedical uses has attracted much attention due to the tunable properties of the dendrimer generation, terminal groups, and inner cavity for the incorporation of a variety of molecules. 1-6 PAMAM dendrimers, for example, have been comprehensively investigated as diagnostic tools and drug carriers. 6-8 Recently, we have reported the third generation poly(benzyl ether) dendrimer porphyrins (DPs) as an effective photosensitizer for photodynamic therapy (PDT). 9-11 PDT involves the administration of a photosensitizer, which preferentially accumulates in target tissues. Subsequent * To whom correspondence should be addressed. Phone: +81-3-5841-7138. Fax: +81-3-5841-7139. E-mail: kataoka@bmw.t.u-tokyo.ac.jp. † Department of Materials Engineering, The University of Tokyo. ‡ Yonsei University. § Center for Disease Biology and Integrative Medicine, The University of Tokyo. | National Defense Medical College. ⊥ Tokyo University of Science. # Department of Chemistry and Biotechnology, The University of Tokyo. + CREST. @ Center for NanoBio Integration, The University of Tokyo. (1) Dendrimers and other Dendritic Polymers; Fre ´chet, J. M. J., Tomalia, D. A., Eds.; John Wiley & Sons: New York, 2001. (2) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem. ReV. 1999, 99, 1665-1688. (3) Lee, I.; Athey, B. D.; Wetzel, A. W.; Meixner, W.; Baker, J. R., Jr. Macromolecules 2002, 35, 4510-4520. (4) Roy, R.; Zanini, D.; Meunier, S. J.; Romanowska, A. J. Chem. Soc., Chem. Commun. 1993, 1869-1872. (5) Jang, W.-D.; Kataoka, K. J. Drug DeliVery Sci. Technol. 2005, 15, 19-30. (6) Wiener, E. C.; Brechbiel, M. W.; Brothers, H.; Magin, R. L.; Gansow, O. A.; Tomalia, D. 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