Enzyme-Triggered Transcytosis of Dendrimer-Drug Conjugate for Deep Penetration into Pancreatic Tumors
Enzyme-Triggered Transcytosis of Dendrimer-Drug Conjugate for Deep Penetration into Pancreatic Tumors
复制标题
酶触发树状聚合物-药物缀合物的转胞吞作用深入渗透胰腺肿瘤
DOI：
10.1021/acsnano.0c00974
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发表时间：
2020-04-28
期刊：
影响因子：
17.1
通讯作者：
Huang, Pintong
中科院分区：
文献类型：
--
作者：
Wang, Guowei;Zhou, Zhuxian;Huang, Pintong
胰腺导管腺癌(PDA)致密的纤维间质阻碍了药物向肿瘤的扩散，导致预后不佳。为了解决这个问题，我们展示了一种树状大分子-喜树碱(CPT)结合物，它通过伽马-谷氨酰转肽酶(GGT)触发的细胞内吞和跨细胞吞噬作用，主动渗透到PDA肿瘤的深处。通过反应性氧物种(ROS)敏感的连接物将CPT与聚酰胺胺(PAMAM)树枝状大分子共价连接，然后用谷胱甘肽对其进行表面修饰，合成了树状大分子-药物结合物。一旦偶联物被输送到PDA肿瘤周围，血管内皮细胞或肿瘤细胞上过表达的GGT就会触发谷胱甘肽的伽马-谷氨酰转移反应，产生伯胺。带正电荷的结合物通过小窝介导的内吞作用和随后的囊泡介导的细胞穿透作用被迅速内化，增强了其在肿瘤实质中的深度渗透，并在被细胞内ROS切割后在整个肿瘤中释放出活性的CPT。与治疗晚期胰腺癌的标准一线化疗药物(吉西他滨)相比，树枝状大分子药物结合物在多种小鼠肿瘤模型中显示出高抗肿瘤活性，包括患者来源的PDA异种移植和PDA细胞原位移植。这项研究证明了一种通过跨细胞转运和ROS响应性药物释放的活性树枝状大分子药物结合物用于PDA治疗的高效率。
The dense fibrotic stroma in pancreatic ductal adenocarcinoma (PDA) resists drug diffusion into the tumor and leads to an unsatisfactory prognosis. To address this problem, we demonstrate a dendrimer-camptothecin (CPT) conjugate that actively penetrates deep into PDA tumors through gamma-glittamyl transpeptidase (GGT)-triggered cell endocytosis and transcytosis. The dendrimer-drug conjugate was synthesized by covalent attachment of CPT to polyamidoamine (PAMAM) dendrimers through a reactive oxygen species (ROS)-sensitive linker followed with surface modification with glutathione. Once the conjugate was delivered to the PDA tumor periphery, the overexpressed GGT on the vascular endothelial cell or tumor cell triggers the gamma-glutamyl transfer reactions of glutathione to produce primary amines. The positively charged conjugate was rapidly internalized via caveolae-mediated endocytosis and followed by vesicle-mediated transcytosis, augmenting its deep penetration within the tumor parenchyma and releasing active CPT throughout the tumor after cleavage by intracellular ROS. The dendrimer-drug conjugate exhibited high antitumor activity in multiple mice tumor models, including patient-derived PDA xenograft and orthotopic PDA cell xenograft, compared to the standard first-line chemotherapeutic drug (gemcitabine) for advanced pancreatic cancer. This study demonstrates the high efficiency of an active tumor-penetrating dendrimer-drug conjugate via transcytotic transport with ROS-responsive drug release for PDA therapy.