近日，浙江大学周珠贤团队研究了双酶-反应性聚合物-药物偶联物诱导多种细胞相互胞吞，实现胰腺深部肿瘤穿透。该研究于2025年5月26日发表在《德国应用化学》杂志上。

酶响应活性转运纳米药物通过诱导癌症细胞的细胞间转移将药物输送到实体瘤深处，有望克服肿瘤密集的细胞外基质屏障。然而，仅对癌症细胞相关酶反应的纳米药物在胰腺肿瘤中不是很有效，因为在分散在大量癌症相关成纤维细胞（CAFs）中的癌症细胞中无法建立连续的跨细胞作用。 

研究组报道了双酶响应的7-乙基-10-羟基喜树碱（SN38）-聚合物缀合物，其能够诱导癌症细胞和CAF之间的跨细胞作用以有效地浸润胰腺肿瘤。共轭物是两性离子的，用于长时间血液循环。一旦进入肿瘤，肿瘤内皮细胞和癌症细胞上过表达的γ-谷氨酰转肽酶（GGT），或CAF上的成纤维细胞活化蛋白酶（FAP），可以裂解γ-谷酰胺或丙氨酰甘氨酸二肽酰胺，产生伯胺。

阳离子化缀合物然后诱导癌症细胞和CAF之间的胞吞作用，建立连续的细胞间转运以浸润肿瘤。结合物的酶反应性和整体疏水性决定了它们的阳离子化和转胞吞行为。具有高疏水性和快速阳离子化的缀合物在癌症患者来源的异种移植物和原位肿瘤模型中显示出强大的抗肿瘤活性。 该研究提供了一种主动运输策略，以克服富含基质细胞的肿瘤的递送障碍。

附：英文原文

Title: Dual Enzyme-Responsive Polymer-Drug Conjugates Induce Diverse Cells Mutual Transcytosis to Achieve Deep Pancreatic Tumor Penetration

Author: Rui Sun, Yifan Zhang, Ying Piao, Jiajia Xiang, Shiqun Shao, Quan Zhou, Jianbin Tang, Chengyuan Dong, Zhuxian Zhou, Youqing Shen

Issue&Volume: 2025-05-26

Abstract: Enzyme-responsive active transporting nanomedicines have shown promise in overcoming the tumor-dense extracellular matrix barrier by inducing cancer cells’ intercellular transcytosis to deliver drugs deep into solid tumors. However, nanomedicine only responsive to the cancer cell-related enzyme is not very effective in pancreatic tumors because successive transcytosis cannot be established among the cancer cells, which are scattered in a large number of cancer-associated fibroblasts (CAFs). Here are reported dual-enzyme responsive 7-ethyl-10-hydroxycamptothecin (SN38)-polymer conjugates capable of inducing transcytosis among cancer cells and CAFs to infiltrate pancreatic tumors efficiently. The conjugates are zwitterionic for long blood circulation. Once in the tumor, the γ-glutamyl transpeptidase (GGT) overexpressed on the tumor endothelial and cancer cells, or the fibroblast-activated protease (FAP) on CAFs, can cleave the γ-glutamylamide or the prolylglycine dipeptide amides, producing primary amines. The cationized conjugate then induces transcytosis among cancer cells and CAFs, establishing successive intercellular transport to infiltrate the tumor. The conjugates' enzyme reactivity and overall hydrophobicity determine their cationization and transcytosis behaviors. The conjugates with high hydrophobicity and fast cationization show potent antitumor activity in pancreatic cancer patient-derived xenograft and orthotopic tumor models. This study provides an active transportation strategy to overcome the delivery barrier of tumors with rich stroma cells.

DOI: 10.1002/anie.202506038

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202506038