Wang Guowei, Zhou Zhuxian, Zhao Zhihao, Li Qunying, Wu Yulian, Yan Sheng, Shen Youqing, Huang Pintong
Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China.
ACS Nano. 2020 Apr 28;14(4):4890-4904. doi: 10.1021/acsnano.0c00974. Epub 2020 Apr 20.
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 γ-glutamyl 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 γ-glutamyl transfer reactions of glutathione to produce primary amines. The positively charged conjugate was rapidly internalized 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 transcytotic transport with ROS-responsive drug release for PDA therapy.
胰腺导管腺癌（PDA）中致密的纤维化基质阻碍药物扩散至肿瘤内部，导致预后不佳。为解决这一问题，我们展示了一种树枝状聚合物-喜树碱（CPT）偶联物，它可通过γ-谷氨酰转肽酶（GGT）触发的细胞内吞作用和转胞吞作用，主动深入PDA肿瘤内部。树枝状聚合物-药物偶联物通过将CPT通过活性氧（ROS）敏感的连接子共价连接到聚酰胺胺（PAMAM）树枝状聚合物上，随后用谷胱甘肽进行表面修饰而合成。一旦偶联物被递送至PDA肿瘤周边，血管内皮细胞或肿瘤细胞上过度表达的GGT会触发谷胱甘肽的γ-谷氨酰转移反应，产生伯胺。带正电荷的偶联物通过小窝介导的内吞作用迅速内化，随后通过囊泡介导的转胞吞作用，增强其在肿瘤实质内的深度渗透，并在被细胞内ROS切割后在整个肿瘤中释放活性CPT。与晚期胰腺癌的标准一线化疗药物（吉西他滨）相比，树枝状聚合物-药物偶联物在多种小鼠肿瘤模型中均表现出高抗肿瘤活性，包括患者来源的PDA异种移植瘤和原位PDA细胞异种移植瘤。本研究证明了一种具有主动肿瘤穿透能力的树枝状聚合物-药物偶联物通过ROS响应性药物释放进行转胞吞运输用于PDA治疗的高效性。
