title: Anti-angiogenesis through noninvasive to minimally invasive intraocular delivery of the peptide CC12 identified by in vivo-directed evolution.
abstract: Anti-vascular endothelial growth factor (VEGF) therapies are widely used for the treatment of neovascular fundus diseases such as diabetic retinopathy. However, these agents need to be injected intravitreally, because their strong hydrophilicity and high molecular weight prevent them from penetrating cell membranes and complex tissue barriers. Moreover, the repeated injections that are required can cause infection and tissue injury. In this study, we used in vivo-directed evolution phage display technology to identify a novel dodecapeptide, named CC12, with the ability to penetrate the ocular barrier in a noninvasive (via conjunctival sac instillation) or minimally invasive (via retrobulbar injection) manner. KV11, an antiangiogenesis peptide previously demonstrated to inhibit pathological neovascularization in the retina, was then used as a model antiangiogenesis cargo for CC12. We found that conjugation of KV11 peptide with CC12 peptide facilitated the delivery of KV11 to the retina, resulting in significant inhibition of retinal neovascularization development via topical application without tissue toxicity. Collectively, our data of multilevel evaluations demonstrate that CC12 may enable the noninvasive to minimally invasive intraocular delivery of antiangiogenic therapeutics.
authors: Department of Ophthalmology, Shanghai Key Laboratory of Fundus Disease, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200080, PR China.
authors: Chong
authors: C
authors: Chen
authors: Department of Ophthalmology, Shanghai Key Laboratory of Fundus Disease, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200080, PR China.
authors: Kun
authors: K
authors: Liu
authors: Department of Ophthalmology, Shanghai Key Laboratory of Fundus Disease, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200080, PR China.
authors: Yupeng
authors: Y
authors: Xu
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital Affiliated to Medical School of Shanghai Jiao Tong University, Shanghai 200032, PR China.
authors: Pengwei
authors: P
authors: Zhang
authors: Department of Ophthalmology, Shanghai Key Laboratory of Fundus Disease, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200080, PR China.
authors: Yan
authors: Y
authors: Suo
authors: Department of Ophthalmology, Shanghai Key Laboratory of Fundus Disease, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200080, PR China.
authors: Yi
authors: Y
authors: Lu
authors: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
authors: Wenyuan
authors: W
authors: Zhang
authors: Department of Ophthalmology, Shanghai Key Laboratory of Fundus Disease, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200080, PR China.
authors: Li
authors: L
authors: Su
authors: Department of Ophthalmology, Shanghai Key Laboratory of Fundus Disease, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200080, PR China.
authors: Qing
authors: Q
authors: Gu
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital Affiliated to Medical School of Shanghai Jiao Tong University, Shanghai 200032, PR China.
authors: Huamao
authors: H
authors: Wang
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital Affiliated to Medical School of Shanghai Jiao Tong University, Shanghai 200032, PR China.
authors: Jianren
authors: J
authors: Gu
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital Affiliated to Medical School of Shanghai Jiao Tong University, Shanghai 200032, PR China. Electronic address: zonghaili@163.com.
authors: Zonghai
authors: Z
authors: Li
authors: Department of Ophthalmology, Shanghai Key Laboratory of Fundus Disease, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200080, PR China. Electronic address: drxuxun@sjtu.edu.cn.
authors: Xun
authors: X
authors: Xu
mesh_terms: D060433:Administration, Ophthalmic; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000737:chemistry* / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001054:Apolipoproteins A / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019020:Directed Molecular Evolution / Q000379:methods*; D056965:Injections, Intraocular / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D010446:Peptide Fragments / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D001054:Apolipoproteins A; C534296:KV11 peptide, human; D009842:Oligopeptides; D010446:Peptide Fragments
keywords: Angiogenesis inhibitor; Cell-penetrating peptides; Intraocular drug delivery; In vivo-direction evolution; Neovascularization; Phage display