Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China; Department of Urinary Surgery, The First Hospital of Jilin University, Changchun 130021, China.
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
J Control Release. 2017 Aug 10;259:136-148. doi: 10.1016/j.jconrel.2016.12.041. Epub 2017 Jan 3.
Bladder cancer (BC) has become a serious public health problem due to its continuously rising incidence, high recurrence rate, and poor quality of life. Intravesical instillation of chemotherapy, one of common and important treatment strategy for BC, is restricted partially due to the short residence time and the low penetration ability of current antineoplastic agent formulations in clinic. Herein, a positively charged disulfide-core-crosslinked polypeptide nanogel of poly(l-lysine)-poly(l-phenylalanine-co-l-cystine) (PLL-P(LP-co-LC)) was synthesized. 10-Hydroxycamptothecin (HCPT) was loaded into the core via a facile diffusion to obtain loading nanogel (i.e., NG/HCPT). The reduction-responsive cationic polypeptide nanogel not only showed a high drug-loading efficiency, a prolonged residence time, and an improved tissue penetration capability, but also demonstrated an ability to accurately and rapidly release HCPT in bladder cancer cells. NG/HCPT exhibited superior cytotoxicity against human T24 bladder cancer cells compared to that of free HCPT in vitro. Moreover, the positively charged loading nanogel exhibited significantly enhanced antitumor efficacy and reduced side effects toward orthotopic bladder cancer model in vivo. Overall, the smart polypeptide nanogel with enhanced residence and permeability provides a promising drug delivery platform for local chemotherapy of BC.
膀胱癌 (BC) 由于发病率不断上升、复发率高和生活质量差，已成为一个严重的公共卫生问题。膀胱内化疗是 BC 常见且重要的治疗策略之一，但由于目前抗肿瘤药物制剂在临床上的驻留时间短和穿透能力低，其应用受到一定限制。在此，合成了一种带正电荷的二硫键核交联多肽纳米凝胶聚（L-赖氨酸）-聚（L-苯丙氨酸-co-L-胱氨酸）（PLL-P(LP-co-LC)）。通过简单的扩散将 10-羟基喜树碱（HCPT）装载到核心中，得到载药纳米凝胶（即 NG/HCPT）。还原响应性阳离子多肽纳米凝胶不仅表现出高载药效率、延长的驻留时间和改善的组织穿透能力，而且还表现出在膀胱癌细胞中准确快速释放 HCPT 的能力。NG/HCPT 在体外对人 T24 膀胱癌细胞的细胞毒性优于游离 HCPT。此外，正电荷载药纳米凝胶在体内荷瘤膀胱癌模型中表现出显著增强的抗肿瘤疗效和降低的副作用。总之，具有增强的驻留和渗透性的智能多肽纳米凝胶为 BC 的局部化疗提供了有前途的药物递送平台。
