Guo Hui, Li Faping, Qiu Heping, Xu Weiguo, Li Pengqiang, Hou Yuchuan, Ding Jianxun, Chen Xuesi
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China.
Department of Urinary Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, China.
Research (Wash D C). 2020 Aug 3;2020:8970135. doi: 10.34133/2020/8970135. eCollection 2020.
Intravesical chemotherapy has been recommended after the gold standard of transurethral resection of the bladder tumor to prevent bladder cancer (BC) from local recurrence in the clinic. However, due to rapid urine excretion and barrier protection of the bladder wall, the clinical performances of chemotherapeutic drugs are severely compromised. In the present work, a smart positively charged disulfide-crosslinked nanogel of oligoarginine-poly(ethylene glycol)-poly(L-phenylalanine--L-cystine) (R-PEG-P(LP--LC)) was prepared to prolong the retention period and enhance the penetration capability of chemotherapeutic agent toward the bladder wall. PEG significantly improved the aqueous dispersibility of the 10-hydroxycamptothecin (HCPT)-loaded R-PEG-P(LP--LC) (, RNG/HCPT) and enhanced the mucoadhesive capability by the nonspecific interaction between PEG chain and the bladder mucosa accompanied with the electrostatic interaction between the cationic R and negatively charged bladder mucosa. Besides, R, as a cell-penetrating peptide, efficiently penetrated through the cell membrane and delivered carried cargo. The disulfide bond endowed the selective release behavior of HCPT triggered by the intracellular reductive microenvironment. As an advanced chemotherapeutic nanoformulation, the smart RNG/HCPT demonstrated superior cytotoxicity against human BC 5637 cells and remarkably enhanced tumor suppression activity toward orthotopic BC models of mouse and rat , indicating its great potential in the clinical intravesical BC chemotherapy.
在临床上，膀胱内化疗已被推荐用于在膀胱肿瘤经尿道切除这一金标准治疗后预防膀胱癌局部复发。然而，由于尿液快速排泄以及膀胱壁的屏障保护作用，化疗药物的临床疗效严重受损。在本研究中，制备了一种智能的带正电荷的二硫键交联纳米凝胶，即寡聚精氨酸-聚乙二醇-聚（L-苯丙氨酸-L-胱氨酸）（R-PEG-P(LP-LC)），以延长化疗药物在膀胱内的滞留时间并增强其对膀胱壁的穿透能力。聚乙二醇（PEG）显著改善了负载10-羟基喜树碱（HCPT）的R-PEG-P(LP-LC)（RNG/HCPT）在水中的分散性，并通过PEG链与膀胱黏膜之间的非特异性相互作用以及阳离子R与带负电荷的膀胱黏膜之间的静电相互作用增强了黏附能力。此外，R作为一种细胞穿透肽，能够有效地穿透细胞膜并递送所载药物。二硫键赋予了HCPT在细胞内还原微环境触发下的选择性释放行为。作为一种先进的化疗纳米制剂，智能的RNG/HCPT对人膀胱癌5637细胞表现出优异的细胞毒性，并对小鼠和大鼠的原位膀胱癌模型具有显著增强的肿瘤抑制活性，表明其在临床膀胱内膀胱癌化疗中具有巨大潜力。
