Tumor-homing photosensitizer-conjugated glycol chitosan nanoparticles for synchronous photodynamic imaging and therapy based on cellular on/off system So Jin Lee a, b, 1 , Heebeom Koo a,1 , Dong-Eun Lee a , Solki Min a, c , Seulki Lee d , Xiaoyuan Chen d , Yongseok Choi b , James F. Leary e , Kinam Park e , Seo Young Jeong c , Ick Chan Kwon a , Kwangmeyung Kim a, * , Kuiwon Choi a, * a Biomedical Research Center, Korea Institute of Science and Technology, 39-1 Hawolgok-dong, Seongbuk-gu, Seoul 136-791, South Korea b School of Life Science and Biotechnology, Korea University,1 Anam-dong, Seongbuk-gu, Seoul 136-701, South Korea c Department of Life and Nanopharmaceutical Science, Kyung Hee University,1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, South Korea d Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), 31 Center Drive, Suite 1C14, Bethesda, MD 20892-2281, United States e Departments of Biomedical Engineering and Pharmaceutics, Purdue University, West Lafayette, IN 47907, United States article info Article history: Received 17 December 2010 Accepted 4 February 2011 Available online 3 March 2011 Keywords: Photosensitizer Nanoparticle Photodynamic therapy Drug delivery Glycol chitosan Cellular on-off system abstract Herein, we developed the photosensitizer, protoporphyrin IX (PpIX), conjugated glycol chitosan (GC) nanoparticles (PpIXeGCeNPs) as tumor-homing drug carriers with cellular on/off system for photody- namic imaging and therapy, simultaneously. In order to prepare PpIXeGCeNPs, hydrophobic PpIXs were chemically conjugated to GC polymer and the amphiphilic PpIXeGC conjugates formed a stable nano- particle structure in aqueous condition, wherein conjugated PpIX molecules formed hydrophobic inner- cores and they were covered by the hydrophilic GC polymer shell. Based on the nanoparticle structure, PpIXeGCeNPs showed the self-quenching effect that is ‘off’ state with no fluorescence signal and phototoxicity with light exposure. It is due to the compact crystallized PpIX molecules in the nano- particles as confirmed by dynamic light scattering and X-ray diffraction methods. However, after cellular uptake, compact nanoparticle structure gradually decreased to generate strong fluorescence signal and singlet oxygen generation when irradiated. Importantly, PpIXeGCeNPs-treated mice presented pro- longed blood circulation, enhanced tumor targeting ability, and improved in vivo therapeutic efficiency in tumor-bearing mice, compared to that of free PpIX-treated mice. These results proved that this tumor- homing cellular ‘on/off’ nanoparticle system of PpIXeGCeNPs has a great potential for synchronous photodynamic imaging and therapy in cancer treatment. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Photodynamic therapy (PDT) is becoming widely known for its application in cancer therapy [1e4]. PDT is a medical treatment using chemical photosensitizer and light irradiation at certain wavelength onto target tumor tissues [5]. The light irradiation causes the photosensitizer to generate cytotoxic singlet oxygen that destroys tumor cells through apoptosis or necrosis [6]. In addition, the selective accumulation of photosensitizers like protoporphyrin IX (PpIX) in tumor tissues provides an intense fluorescence signal that also can be employed in photodynamic imaging (PDI) [7]. However, these photosensitizers are limited in clinical use because of non-specific skin phototoxicity, poor water solubility, and inef- ficient delivery to target tumor tissues in cancer treatment [8,9]. There are two strategies used for overcoming these limitations. The one is to enhance the tumor specificity of photosensitizer by using nano-sized drug carriers that are known to accumulate at the tumor site by the so-called enhanced permeation and retention (EPR) effect, resulting in efficient passive accumulation in solid tumor tissues [10]. It has been reported that various photosensi- tizer-encapsulated nano-sized carriers could enhance the tumor target specificity and therapeutic efficacy in cancer treatment, compared to free photosensitizer [2,3,11]. On the other hand, there are some efforts to control the photosensitizer’s activity using quenching/dequenching system, which show the specific recovery of the photosensitizer’s activity in target tumor tissue [7]. For this purpose, the quenched nano-sized drug carriers have been * Corresponding authors. Tel.: þ82 2 958 5916; fax: þ82 2 958 5909. E-mail addresses: kim@kist.re.kr (K. Kim), choi@kist.re.kr (K. Choi). 1 These authors contributed equally to this paper. Contents lists available at ScienceDirect Biomaterials journal homepage: www.elsevier.com/locate/biomaterials 0142-9612/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2011.02.009 Biomaterials 32 (2011) 4021e4029