Collagen-targeted tumor-specific transepithelial penetration enhancer mediated intravesical chemoimmunotherapy for non-muscle-invasive bladder cancer
Collagen-targeted tumor-specific transepithelial penetration enhancer mediated intravesical chemoimmunotherapy for non-muscle-invasive bladder cancer
复制标题
DOI：
10.1016/j.biomaterials.2022.121422
复制
发表时间：
2022-02-24
期刊：
影响因子：
14
通讯作者：
Wu, Song
中科院分区：
文献类型：
--
作者：
Li, Guangzhi;Tao, Tao;Wu, Song
膀胱灌注化疗药物或免疫刺激剂可降低经尿道膀胱肿瘤电切术后非肌层浸润性膀胱癌（NMIBC）的复发率。然而，由于膀胱上皮屏障，其疗效仍有待提高。尽管某些经粘膜递送载体能够增强膀胱内药剂的经上皮渗透，但它们几乎不能区分膀胱壁的癌和邻近的正常组织。本文报道了聚乙二醇（PEG）和戊二醛共修饰的氟化壳聚糖（PGFCS）作为一种胶原靶向的经上皮渗透促进剂，通过与肿瘤组织中富集的胶原胺发生亲脂选择性反应，形成肿瘤靶向的粘附界面，从而通过氟化壳聚糖介导的紧密连接调节打开肿瘤部位的经上皮传递屏障。有趣的是，在PGFCS预处理的帮助下，膀胱内滴注化疗药物吡拉布星（THP）联合免疫刺激剂白细胞介素-12可以引发有效的抗肿瘤化学免疫应答，破坏原位膀胱肿瘤并抑制癌症复发。我们的工作提出了一种独特类型的肿瘤特异性跨上皮渗透促进剂，其显示出安全有效的膀胱内灌注NMIBC的巨大潜力。
Intravesical instillation of chemotherapeutics or immune-stimulating agents could reduce the recurrence rate of non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of the bladder tumors. Its efficacy, however, remains to be improved due to the bladder epithelial barrier. Although certain transmucosal delivery carriers are able to enhance the transepithelial penetration of intravesical agents, they could hardly differentiate carcinoma and adjacent normal tissues of the bladder wall. Here, we reported polyethylene glycol (PEG) & glutaraldehyde co-modified fluorinated chitosan (PGFCS) as a collagen-targeted transepithelial penetration enhancer, which could create a tumor-targeted adhesive interface by the aldehyde-selective reaction with collagen amines enriched in the tumor, thus opening the transepithelial-delivery barrier at the tumor site though the fluorinated-chitosan-mediated tight junction regulation. Interestingly, with the help of PGFCS pre-treatment, intravesical instillation of chemotherapeutics pirabucin (THP) combined with immune stimulating agent interleukin-12 could trigger potent antitumor chemoimmunotherapeutic responses in destructing orthotopic bladder tumors and inhibiting cancer recurrence. Our work presents a unique type of tumor-specific trans epithelial penetration enhancer, which shows great potential for safe and effective intravesical instillation of NMIBC.