Department of Ophthalmology, Affiliated Hospital of Jiangnan University, Wuxi 214062, China.
Department of Ophthalmology, Affiliated Hospital of Jiangnan University, Wuxi 214062, China.
Int J Biol Macromol. 2019 Dec 1;141:997-1003. doi: 10.1016/j.ijbiomac.2019.09.085. Epub 2019 Sep 12.
Melphalan (MEL) is an effective chemotherapeutic agent for treatment of retinoblastoma (Rb) which is the most common childhood malignancy. However, the inherent cardiopulmonary toxicity and hazardous integration limit its therapeutic effect on RB. N-Acetylheparosan (AH), a natural heparin-like polysaccharide in mammals with long circulation effect and good biocompatibility, was linked by d-α-tocopherol acid succinate (VES) via and cystamine (CYS) to synthesize reduction-responsive N-acetylheparosan-CYS-Vitamin E succinate (AHV) copolymers. In addition, CYS was replaced by adipic acid dihydrazide (ADH) to obtain a control of non-reduction-responsive polymers N-acetylheparosan-ADH-Vitamin E succinate (ADV). MEL-loaded AHV micelles (MEL/AHV) as well as ADV micelles (MEL/ADV) were prepared with small particle size and high drug loading content. In vitro drug release showed that MEL/AHV micelles presented obvious reduction-triggered release behavior compared with MEL/ADV. In vitro antitumor effects were investigated using WERI-Rb-1 retinoblastoma cells. Cytotoxicity experiments showed that the IC of MEL/AHV was significantly lower than that of free MEL and MEL/ADV, suggesting that MEL/AHV enhanced the cytotoxicity against retinoblastoma cells. Furthermore, MEL/AHV micelles were more easily uptaken by multiple pathways compared with MEL/ADV and free MEL. Therefore, MEL/AHV might be a potential delivery system for enhanced delivery of melphalan to Rb cells.
美法仑（MEL）是治疗视网膜母细胞瘤（Rb）的有效化疗药物，Rb 是最常见的儿童恶性肿瘤。然而，其固有的心肺毒性和危险的整合限制了它在 RB 治疗中的效果。N-乙酰肝素（AH），一种哺乳动物中具有长循环效应和良好生物相容性的天然肝素样多糖，通过 d-α-生育酚酸琥珀酸酯（VES）和半胱胺（CYS）连接，合成还原响应性 N-乙酰肝素-CYS-生育酚琥珀酸酯（AHV）共聚物。此外，用己二酰肼（ADH）取代 CYS，得到非还原响应性聚合物 N-乙酰肝素-ADH-生育酚琥珀酸酯（ADV）的对照。载有 MEL 的 AHV 胶束（MEL/AHV）和 ADV 胶束（MEL/ADV）具有粒径小、载药含量高的特点。体外药物释放实验表明，与 MEL/ADV 相比，MEL/AHV 胶束表现出明显的还原触发释放行为。体外抗肿瘤作用研究采用 WERI-Rb-1 视网膜母细胞瘤细胞。细胞毒性实验表明，MEL/AHV 的 IC 明显低于游离 MEL 和 MEL/ADV，表明 MEL/AHV 增强了对视网膜母细胞瘤细胞的细胞毒性。此外，与 MEL/ADV 和游离 MEL 相比，MEL/AHV 胶束更容易通过多种途径被摄取。因此，MEL/AHV 可能是增强 MEL 向 Rb 细胞传递的潜在给药系统。
