Guo Hui, Li Faping, Xu Weiguo, Chen Jinjin, Hou Yuchuan, Wang Chunxi, Ding Jianxun, Chen Xuesi
Department of Urinary Surgery the First Hospital of Jilin University Changchun 130021 P. R. China.
Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun 130022 P. R. China.
Adv Sci (Weinh). 2018 Mar 27;5(6):1800004. doi: 10.1002/advs.201800004. eCollection 2018 Jun.
Initially, chemotherapy is effective for treatment of bladder cancer after transurethral resection of the bladder. However, certain patients progressively become unresponsive after multiple treatment cycles, which results from the rapid and almost complete excretion of clinically used formulations of antineoplastic agents with urinary voiding. Improving the mucoadhesiveness and penetrability of chemotherapeutic drugs are key factors in treatment of advanced bladder cancer. Here, a smart disulfide-crosslinked polypeptide nanogel of poly(l-lysine)-poly(l-phenylalanine--l-cystine) (PLL-P(LP--LC)) is developed to deliver 10-hydroxycamptothecin (HCPT) for treatment of orthotopic bladder cancer. The positively charged PLL-P(LP--LC) can significantly prolong the retention period and enhance the tissue permeability of HCPT within the bladder wall of rat. Moreover, the reduction-responsive polypeptide nanogel (i.e., NG/HCPT) possesses the capability to accurately and rapidly deliver HCPT in bladder cancer cells. NG/HCPT can significantly inhibit proliferation of human bladder cancer 5637 cells in vitro and enhance antitumor activity toward an orthotopic rat bladder cancer model in vivo. This work demonstrates that the smart polypeptide nanogel may function as a promising drug-delivery system for local chemotherapy of bladder cancer with unprecedented clinical benefits.
最初，化疗对经尿道膀胱切除术后的膀胱癌治疗有效。然而，某些患者在多个治疗周期后逐渐变得无反应，这是由于临床上使用的抗肿瘤药物制剂随排尿迅速且几乎完全排出所致。提高化疗药物的粘膜粘附性和渗透性是晚期膀胱癌治疗的关键因素。在此，开发了一种聚（L-赖氨酸）-聚（L-苯丙氨酸-L-胱氨酸）（PLL-P(LP-LC)）的智能二硫键交联多肽纳米凝胶，用于递送10-羟基喜树碱（HCPT）以治疗原位膀胱癌。带正电荷的PLL-P(LP-LC)可显著延长HCPT在大鼠膀胱壁内的滞留时间并增强其组织渗透性。此外，还原响应性多肽纳米凝胶（即NG/HCPT）具有在膀胱癌细胞中准确快速递送HCPT的能力。NG/HCPT可在体外显著抑制人膀胱癌5637细胞的增殖，并增强对体内原位大鼠膀胱癌模型的抗肿瘤活性。这项工作表明，这种智能多肽纳米凝胶可能作为一种有前途的药物递送系统用于膀胱癌的局部化疗，具有前所未有的临床益处。
