Journal
ACS NANO
Volume 14, Issue 4, Pages 4890-4904Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.0c00974
Keywords
dendrimer-camptothecin conjugate; gamma-glutamyl transpeptidase; charge reversal; deep penetration; transcytosis; pancreatic ductal adenocarcinoma
Categories
Funding
- National Key RAMP
- D Program of China [2018YFC0115900]
- National Natural Science Foundation of China [81527803, 81420108018, 21875211]
- Zhejiang Science and Technology Project [2019C03077]
- China Postdoctoral Science Foundation [2019M652116]
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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.
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