1. Academic Validation
  2. Sonodynamic Therapy of NRP2 Monoclonal Antibody-Guided MOFs@COF Targeted Disruption of Mitochondrial and Endoplasmic Reticulum Homeostasis to Induce Autophagy-Dependent Ferroptosis

Sonodynamic Therapy of NRP2 Monoclonal Antibody-Guided MOFs@COF Targeted Disruption of Mitochondrial and Endoplasmic Reticulum Homeostasis to Induce Autophagy-Dependent Ferroptosis

  • Adv Sci (Weinh). 2023 Sep 3;e2303872. doi: 10.1002/advs.202303872.
Zhiyu Zhao 1 Yanjie Wu 2 Xiaochen Liang 3 Jiajing Liu 1 Yi Luo 4 Yijia Zhang 1 Tingting Li 1 Cong Liu 1 Xian Luo 1 Jialin Chen 4 Yunjie Wang 1 Shengyu Wang 1 Ting Wu 1 Shaoliang Zhang 5 Dong Yang 1 Wengang Li 1 Jianghua Yan 1 Zhihai Ke 2 Fanghong Luo 1
Affiliations

Affiliations

  • 1 Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361000, P.R. China.
  • 2 School of Science and Engineering, Shenzhen Key Laboratory of Innovative Drug Synthesis, The Chinese University of Hong Kong, Shenzhen, 518172, P.R. China.
  • 3 Environmental Toxicology, University of California, Riverside, California, 92507, USA.
  • 4 School of Basic Medicine, School of Clinical Medicine, Fujian Medical University, Fuzhou, 350122, P.R. China.
  • 5 Shanghai Guangsheng Biopharmaceutical Co., Ltd, Shanghai, 200120, P.R. China.
Abstract

The lethality and chemotherapy resistance of pancreatic Cancer necessitates the urgent development of innovative strategies to improve patient outcomes. To address this issue, we designed a novel Drug Delivery system named GDMCN2,which uses iron-based metal organic framework (Fe-MOF) nanocages encased in a covalent organic framework (COF) and modified with the pancreatic cancer-specific antibody, NRP2. After being targeted into tumor cells, GDMCN2 gradually release the sonosensitizer sinoporphyrin sodium (DVDMS) and chemotherapeutic gemcitabine (GEM) and simultaneously generated Reactive Oxygen Species (ROS) under ultrasound (US) irradiation. This system can overcome gemcitabine resistance in pancreatic Cancer and reduce its toxicity to non-targeted cells and tissues. In a mechanistic cascade, the release of ROS activates the mitochondrial transition pore (MPTP), leading to the release of CA2+ and induction of endoplasmic reticulum (ER) stress. Therefore, microtubule-associated protein 1A/1B-light chain 3 (LC3) is activated, promoting lysosomal Autophagy. This process also induces autophagy-dependent Ferroptosis, aided by the upregulation of Nuclear Receptor Coactivator 4 (NCOA4). This mechanism increases the sensitivity of pancreatic Cancer cells to chemotherapeutic drugs and increases mitochondrial and DNA damage. The findings demonstrate the potential of GDMCN2 nanocages as a new avenue for the development of Cancer therapeutics.

Keywords

covalent organic framework (COF); endoplasmic Reticulum (ER) stress; ferroptosis; gemcitabine; metal organic framework (MOFs); sonodynamic therapy.

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