视网膜母细胞瘤是最常见的儿童眼内恶性肿瘤，极易导致失明甚至威胁生命。临床上采用全身化疗辅助局部治疗（如激光光凝和冷冻治疗等）方案，但普通化疗药眼内分布低，提高剂量易加剧毒副作用。已知致癌蛋白MDM2和MDMX是视网膜母细胞瘤分子靶向治疗新靶点，申请人前期设计获得的D型多肽类p53蛋白激活剂可双效抑制MDM2和MDMX，且生物稳定性高，但因无法入胞，难以发挥抗肿瘤活性。本课题拟设计并合成光敏霍乱毒素B链蛋白衍生物，修饰于载D型多肽的脂质体表面，静脉给药后光敏霍乱毒素B链蛋白衍生物与全身广泛表达的受体无结合，在眼部经蓝光LED快速激活后，生成的原形霍乱毒素B链蛋白可介导脂质体高效、快速跨血-视网膜屏障，并将D型多肽药物靶向递送至视网膜母细胞瘤内，激活p53通路而发挥抗肿瘤活性。本课题拟利用可见光触发蛋白功能恢复，实现眼底（可见光通透性极佳）靶向递药，该思路对其他眼底疾病的治疗有借鉴作用。

Retinoblastoma, a tumor arising from the retina, is the most common primary intraocular tumor of childhood. It often causes blindness and even death of patients. In clinic, systemic chemotherapy in combination with local treatments (i.e. photocoagulation and cryotherapy) is the primary protocol for the management of retinoblastoma. The intraocular biodistribution of ordinary chemotherapeutic agents is low after systemic administration. Elevating the dose may cause severe side effects. The oncoproteins, MDM2 and MDMX, are implicated in the origination and progression of retinoblastoma, and have been recognized as new targets for molecularly targeted therapy of retinoblastoma. We have identified a D-peptide antagonist that is resistant to proteolytic degradation and can specifically bind to MDM2 and MDMX with high affinities. However, this D-peptide is impermeable to cell membrane to interact with intracellular oncoproteins. Here we aim to develop a photoactivatable derivative of cholera toxin subunit B (CTB) and conjugate it on the surface of D-peptide loaded liposomes. After systemic administration, the derivative of CTB would not bind to the widely expressed receptor (ganglioside GM1) in normal organs. Irradiation with visible LED light on the eye can rapidly activate CTB and recover its bioactivity in the posterior segment of the eye, leading to targeted delivery of D-peptide into retinoblastoma. The intracellular D-peptide can specifically antagonize MDM2 and MDMX, activate the p53 pathway and kill the retinoblastoma cells. Since the visible light is able to penetrate the eyeball efficiently, the photoactivatable derivative of CTB designed in this project would be also useful for the therapy of other diseases in the posterior segment of the eye.