The movement of self-assembled amphiphilic polymeric nanoparticles in the vitreous and retina after intravitreal injection Heebeom Koo a,1 , Hyungwon Moon b,1 , Hyounkoo Han b , Jin Hee Na a , Myung Sook Huh a , Jae Hyung Park c , Se Joon Woo d , Kyu Hyung Park d , Ick Chan Kwon a , Kwangmeyung Kim a, * , Hyuncheol Kim b, ** a Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, Republic of Korea b Chemical and Biomolecular Engineering, Sogang University, #1 Shinsu-dong, Mapo-gu, Seoul 121-742, Republic of Korea c Department of Polymer Science and Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea d Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam 463-707, Republic of Korea article info Article history: Received 23 December 2011 Accepted 14 January 2012 Available online 7 February 2012 Keywords: Ocular Intravitreal Nanoparticle Drug delivery Vitreous Retina abstract The purpose of this study is to determine the correlation between the distribution of nanoparticles in the vitreous and retina and their surface properties after intravitreal injection. For this purpose, we synthesized seven kinds of nanoparticles through self-assembly of amphiphilic polymer conjugates in aqueous condition. They showed similar size but different surface properties. They were labeled with fluorescent dyes for efficient tracking. After intravitreal injection of these nanoparticles into a rodent eye, their time-dependent distribution in the vitreous and retina was determined in stacking tissue images by confocal microscopy. The results demonstrated that the surface property of nanoparticles is a key factor in determining their distribution in the vitreous and retina after intravitreal injection. In addition, immunohistochemistry and TEM images of retina tissues suggested the important mechanism related with Mülller cells for intravitreally administered nanoparticles to overcome the physical barrier of inner limiting membrane and to penetrate into the deeper retinal structures. Therefore, we expect that this study can provide valuable information for biomedical researchers to develop optimized nanoparticles as drug or gene carriers for retinal and optic nerve disorders such as glaucoma, age-related macular degeneration, and diabetic retinopathy. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction In spite of state-of-the-art ocular cares accomplished by recent advances in biomedical technology, many peoples still suffer from their vision loss due to various ocular diseases, including glaucoma, age-related macular degeneration, and diabetic retinopathy. Most vision-threatening eye conditions are related to the retina. Many kinds of ocular drug delivery methods to the retina such as topical administration, systemic administration, trans-scleral delivery and intravitreal injection have been researched for several decades. However, in clinic, only the intravitreal injection is currently most favorable to deliver therapeutic agent to the retina as well as reducing the systemic side-effects because of the intrinsic limita- tions of the other methods such as limited uptake or ocular penetration [1,2]. Intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF), such as ranibizumab, is currently the first line treatment in exudative age-related macular degeneration (AMD) [3] and efficacious in many ocular diseases such as diabetic retinopathy, retinal vein occlusion, and choroidal vascularization by other causes like high myopia [4]. Despite the proven efficacy, the most important issues unre- solved regarding intravitreal drug delivery are (1) the intraocular retention time and (2) the effective drug delivery into the target cells. Current intravitreal injections of anti-VEGF agents required monthly dosing are vulnerable to ocular and systemic complica- tions. Longer half-life of a drug formulation such as particulate forms could enable less frequent intravitreal injections, lower cost and less injection-related complications such as sight-threatening endophthalmitis and retinal detachment [5,6]. As the half-life of intravitreal drugs is correlated to the size, nanoparticles that are larger than the size of original drugs can lead to longer intraocular retention. Second, as the amount of solution that can be injected intravitreally is limited (less than 0.1 mL), effective delivery of materials into target cells is essential to achieve adequate * Corresponding author. Tel.: þ82 2 958 5916; fax: þ82 2 958 5909. ** Corresponding author. Tel.: þ82 2 705 8922; fax: þ82 2 3273 0331. E-mail addresses: kim@kist.re.kr (K. Kim), hyuncheol@sogang.ac.kr (H. Kim). 1 These authors contributed equally to this paper. Contents lists available at SciVerse ScienceDirect Biomaterials journal homepage: www.elsevier.com/locate/biomaterials 0142-9612/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2012.01.030 Biomaterials 33 (2012) 3485e3493