Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-do 24341, Korea.
Theranostics. 2023 Apr 17;13(8):2424-2438. doi: 10.7150/thno.81714. eCollection 2023.
Neovascularization is a hallmark of the late stages of diabetic retinopathy (DR) leading to blindness. The current anti-DR drugs have clinical disadvantages including short circulation half-lives and the need for frequent intraocular administration. New therapies with long-lasting drug release and minimal side effects are therefore needed. We explored a novel function and mechanism of a proinsulin C-peptide molecule with ultra-long-lasting delivery characteristics for the prevention of retinal neovascularization in proliferative diabetic retinopathy (PDR). We developed a strategy for ultra-long intraocular delivery of human C-peptide using an intravitreal depot of K9-C-peptide, a human C-peptide conjugated to a thermosensitive biopolymer, and investigated its inhibitory effect on hyperglycemia-induced retinal neovascularization using human retinal endothelial cells (HRECs) and PDR mice. In HRECs, high glucose conditions induced oxidative stress and microvascular permeability, and K9-C-peptide suppressed those effects similarly to unconjugated human C-peptide. A single intravitreal injection of K9-C-peptide in mice resulted in the slow release of human C-peptide that maintained physiological levels of C-peptide in the intraocular space for at least 56 days without inducing retinal cytotoxicity. In PDR mice, intraocular K9-C-peptide attenuated diabetic retinal neovascularization by normalizing hyperglycemia-induced oxidative stress, vascular leakage, and inflammation and restoring blood-retinal barrier function and the balance between pro- and anti-angiogenic factors. K9-C-peptide provides ultra-long-lasting intraocular delivery of human C-peptide as an anti-angiogenic agent to attenuate retinal neovascularization in PDR.
新生血管形成是糖尿病视网膜病变（DR）晚期的一个标志，导致失明。目前的抗 DR 药物具有临床缺点，包括循环半衰期短和需要频繁的眼内给药。因此，需要新的具有长效药物释放和最小副作用的治疗方法。我们探索了一种具有超长持续传递特性的胰岛素原 C 肽分子的新功能和机制，用于预防增生性糖尿病视网膜病变（PDR）中的视网膜新生血管形成。
我们开发了一种使用 K9-C 肽（一种与人 C 肽缀合的温敏生物聚合物）的玻璃体内储库进行人 C 肽超长眼内传递的策略，并使用人视网膜内皮细胞（HRECs）和 PDR 小鼠研究了其对高血糖诱导的视网膜新生血管形成的抑制作用。
在 HRECs 中，高葡萄糖条件诱导氧化应激和微血管通透性，而 K9-C 肽与人 C 肽类似，抑制了这些作用。K9-C 肽在小鼠单次玻璃体内注射导致人 C 肽的缓慢释放，至少在 56 天内保持眼内空间中生理水平的 C 肽，而不会引起视网膜细胞毒性。在 PDR 小鼠中，眼内 K9-C 肽通过使高血糖诱导的氧化应激、血管渗漏和炎症正常化，恢复血视网膜屏障功能和促血管生成和抗血管生成因子之间的平衡，从而减轻糖尿病性视网膜新生血管形成。
K9-C 肽作为一种抗血管生成剂，提供了超长的人 C 肽眼内传递，以减轻 PDR 中的视网膜新生血管形成。
