Irreversible Electroporation-Induced Inflammation Facilitates Neutrophil-Mediated Drug Delivery to Enhance Pancreatic Cancer Therapy

作者：Teng Huang, Xiaofei Wen, Yuxuan Liang, Xiao Liu, Jun Zhao, Xin Long · 发表于：Molecular Pharmaceutics · 年份：2024 · DOI：10.1021/acs.molpharmaceut.4c00006 · 被引用次数：11 · 研究领域：Microbial Inactivation Methods、Microfluidic and Bio-sensing Technologies、Plasma Applications and Diagnostics

Pancreatic cancer is a deadly disease with a five-year overall survival rate of around 11%. Chemotherapy is a cornerstone in the treatment of this malignancy, but the intratumoral delivery of chemotherapy drugs is impaired by the highly fibrotic tumor-associated stroma. Irreversible electroporation (IRE) is an ablative technique for treating locally advanced pancreatic cancer. During a typical IRE procedure, high-intensity electric pulses are released to kill tumor cells through the irreversible disruption of the cytoplasm membranes. IRE also induces rapid tumor infiltration by neutrophils and offers an opportunity for neutrophil-mediated drug delivery. We herein showed that the IRE-induced neutrophil trafficking was facilitated by the upregulation of neutrophil chemotaxis and migration as well as the release of several chemoattractants. Doxorubicin-loaded bovine serum albumin nanoparticles were prepared and loaded into neutrophils at a ratio of 9.9 ± 1.2 to 11.7 ± 2.0 pg of doxorubicin per cell. The resultant formulation (NP@NEs) efficiently accumulated in the IRE-treated KPC-A377 murine pancreatic tumors with an uptake value of 10.7 ± 1.5 (percent of injected dose per gram of tissue, abbreviated as %ID/g) at 48 h after intravenous injection. In both Panc02 and KPC-A377 murine pancreatic tumor models, the combination of IRE + NP@NEs inhibited tumor growth more effectively than either monotherapy. The tumors treated with the combination also exhibited the lowest frequency of ...