Precise Photodynamic Therapy by Midkine Nanobody-Engineered Nanoparticles Remodels the Microenvironment of Pancreatic Ductal Adenocarcinoma and Potentiates the Immunotherapy.
ACS Nano(2024)SCI 1区
Wuhan Univ | Shenzhen Peoples Hosp | Southern Med Univ | Univ Western Australia | Univ Hong Kong | Guizhou Med Univ
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is notorious for its resistance against chemotherapy and immunotherapy due to its dense desmoplastic and immunosuppressive tumor microenvironment (TME). Traditional photodynamic therapy (PDT) was also less effective for PDAC owing to poor selectivity, insufficient penetration, and accumulation of photosensitizers in tumor sites. Here, we designed a light-responsive novel nanoplatform targeting the TME of PDAC through tumor-specific midkine nanobodies (Nbs), which could efficiently deliver semiconducting polymeric nanoparticles (NPs) to the TME of PDAC and locally produce abundant reactive oxygen species (ROS) for precise photoimmunotherapy. The synthesized nanocomposite can not only achieve multimodal imaging of PDAC tumors (fluorescence and photoacoustic imaging) but also lead to apoptosis and immunogenic cell death of tumor cells via ROS under light excitation, ultimately preventing tumor progression and remodeling the immunosuppressive TME with increased infiltration of T lymphocytes. Combined with a PD-1 checkpoint blockade, the targeted PDT platform showed the best antitumor performance and markedly extended mice survival. Conclusively, this work integrating Nbs with photodynamic NPs provides a novel strategy to target formidable PDAC to achieve tumor suppression and activate antitumor immunity, creating possibilities for boosting efficacy of immunotherapy for PDAC tumors through the combination with precise local PDT.
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Key words
nanobody,midkine,immunotherapy,targeted therapy,pancreatic ductal adenocarcinoma
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论文作者介绍
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Authors include: - Chengming Qu (Research Interests: Photothermal Therapy, Nanobodies, Immunotherapy, Bacteria, Sting) - Yuan Haitao (Research Interests: Cloud Computing, Task Scheduling, Particle Swarm Optimization, Deep Reinforcement Learning, Computation Offloading) - Ming Tian (Research Interests: Immunotherapy, Carnitine Synthesis, Hedgehog Signaling Pathway, Liver Regeneration) - Zhang Xiaodong (Research Interests: Gold Nanoclusters, Electronic Structure, Optical Properties, Simulation, Fresnel Lens) - Peng Xia (Research Interests: Hepatocellular Carcinoma, C-Met, Receptor Tyrosine Kinase, Kinase Inhibitors, Fgfr) - Guangwei Shi (Research Interests: Glioblastoma, Nanobodies, Radioensitivity, Egfrviii, Aptamer) - Rui Hou (Institution: Department of Respiratory Medicine, Shenzhen People's Hospital) - Ji Li (Institution: QEII Medical Centre, University of Western Australia) - Jiang Haibo (Research Interests: Chylomicron, Backscattered Electron Imaging, Nano Secondary Ion Mass Spectrometry Imaging, GPI-Anchored HDL-Binding Protein 1, Triglyceride-Rich Lipoprotein) - Yang Zhiyong (Research Interests: Pancreatic Cancer, Hepatocellular Carcinoma, Aberrant RNA Splicing, Pancreatic Cancer Risk, Biliary Tract Cancer) - Tengxiang Chen (Research Interests: Proliferation, Pancreatic Cancer, Invasion, Metastasis, Prognosis) - Li Zhijie (Research Interests: Cornea, Neutrophils, Inflammation, Wound Healing, Metabolic Syndrome) - Wang Jigang (Research Interests: Autophagy, Proteomics, Triptolide, Artemisinin, Apoptosis) - Yuan Yufeng (Research Interests: Hepatocellular Carcinoma, Covid-19, Prognosis, Metabolic Reprogramming, 2-Methylcitrate)
文献大纲
Research Paper Outline
Abstract
- Multidrug resistance and high risk of recurrence necessitate effective and less toxic alternative treatments for pancreatic cancer.
- Pancreatic cancer cells are highly resistant to apoptosis but sensitive to ferroptosis.
- An arsenene nanoplatform, AsIr@PDA, loaded with the ferroptosis-inducing metal complex IrFN was designed.
- AsIr@PDA exhibits superior ferroptosis induction, good photothermal properties, and high drug loading, effectively inhibiting pancreatic tumors.
Introduction
- 2D single-element nanosheets like arsenene have shown excellent performance in the biomedical field.
- Arsenene possesses antitumor effects, affecting DNA replication, repair, and metabolic pathways.
- Arsenene nanomaterials have tremendous potential in cancer treatment.
- Pancreatic cancer is sensitive to ferroptosis, and the design of nanotherapeutics targeting the ferroptosis pathway is promising.
Results and Discussion
- Arsenene nanosheets and the ferroptosis-inducing metal complex IrFN were synthesized.
- The AsIr@PDA nanoplatform was prepared and characterized.
- AsIr@PDA exhibits excellent ferroptosis induction effects.
- AsIr@PDA possesses good photothermal conversion properties.
- AsIr@PDA can promote antitumor immune responses.
Conclusion
- The designed AsIr@PDA nanoplatform achieves superior therapeutic effects on pancreatic cancer through ferroptosis-inducing chemotherapy and immunotherapy.
- This work provides a strong reference for the application of 2D arsenene nanomaterials in cancer immunotherapy.
关键问题
Q: What research methods were specifically used in the paper?
- Synthesis and Characterization: Two-dimensional arsenene nanosheets were synthesized using the liquid phase exfoliation method and characterized using Transmission Electron Microscopy (TEM), Atomic Force Microscopy (AFM), Energy Dispersive Spectroscopy (EDS), Fourier Transform Infrared Spectroscopy (FTIR), Thermogravimetric Analysis (TGA), and X-ray Photoelectron Spectroscopy (XPS).
- Cell Experiments: The pancreatic cancer cell line Pan02 was used for cytotoxicity tests, cellular uptake experiments, flow cytometry to detect ROS and LPO production, and immunofluorescence staining.
- Animal Experiments: A pancreatic cancer mouse model was constructed, and the nanoplatform was injected via the tail vein to assess biodistribution, antigen presentation process detection, immune cell detection, and tumor growth inhibition.
- Photothermal Performance Test: Near-infrared (NIR) laser irradiation was used to detect the temperature changes and drug release of the nanoplatform.
- Statistical Analysis: Statistical analysis of experimental data was conducted, including cytotoxicity tests and immune cell detection.
Q: What are the main research findings and achievements?
- A successful design and synthesis of the arsenene-iridium nanoplatform (AsIr@PDA) were achieved, which exhibits efficient ferroptosis induction, good photothermal performance, high drug loading capacity, and spatially and temporally controlled drug release.
- The AsIr@PDA nanoplatform induced ferroptosis in pancreatic cancer cells and activated anti-tumor immune responses by enhancing immunogenic cell death efficiency.
- In vivo experiments showed that the AsIr@PDA nanoplatform significantly inhibited pancreatic tumor growth without明显的副作用 (obvious side effects), and also prevented tumor recurrence.
- Compared to traditional cisplatin nanoplatforms, the AsIr@PDA nanoplatform overcame apoptosis resistance and multidrug resistance, providing a new strategy for pancreatic cancer treatment.
Q: What are the current limitations of this research?
- Although the AsIr@PDA nanoplatform showed good therapeutic effects in vitro and in vivo, long-term toxicity studies and large-scale clinical trials have not been conducted, so its long-term safety and clinical application potential need further evaluation.
- The research focuses primarily on a specific type of cancer, pancreatic cancer, and the effectiveness and applicability of the AsIr@PDA nanoplatform in other types of cancer need further exploration.
- Although the study demonstrated that the AsIr@PDA nanoplatform can induce ferroptosis and activate immune responses, the specific molecular mechanisms and signaling pathways require more in-depth research.
- In animal experiments, the biodistribution of the nanoplatform was mainly concentrated in the liver and spleen, which may affect its therapeutic effect on pancreatic tumors and requires further optimization of the nanoplatform's targeting ability.
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