Engineered extracellular vesicles for targeted therapy of pancreatic cancer

Pancreatic cancer is one of the most lethal forms of cancer, with a high mortality rate and limited treatment options. A major reason for its resilience and aggressiveness is its tumor microenvironment (TME), which includes a dense fibrous tissue and specialized cells called cancer-associated fibroblasts (CAFs). These CAFs contribute significantly to the tumor’s growth and resistance to therapy. However, recent breakthroughs in the field of engineered extracellular vesicles (EVs) offer new hope for targeting this tough microenvironment.

Understanding the Tumor Microenvironment

The TME in pancreatic cancer is characterized by extensive fibrosis, which is the formation of excess fibrous connective tissue. This fibrosis not only supports tumor growth but also acts as a barrier to effective drug delivery. CAFs play a central role in creating this fibrotic environment and helping the tumor evade treatments. To combat pancreatic cancer more effectively, scientists are focusing on ways to reprogram these CAFs and modify the TME.

Engineered Extracellular Vesicles: A Novel Approach

Extracellular vesicles are tiny, cell-derived particles that can transfer molecules between cells, influencing their behavior. In this study, researchers at Nantong University engineered EVs to carry therapeutic agents specifically designed to target and reprogram CAFs. These EVs were derived from bone marrow mesenchymal stem cells (BMSCs), which have natural healing properties.

The Therapeutic Agents: miR-138-5p and Pirfenidone

The engineered EVs were loaded with two key therapeutic agents:

  1. miR-138-5p: A microRNA that can regulate gene expression and has anti-cancer properties.
  2. Pirfenidone (PFD): An anti-fibrotic drug that can reduce fibrosis.

Additionally, these EVs were modified on their surface with peptides that target integrin α5, a molecule found on CAFs. This modification enhanced the ability of the EVs to specifically target CAFs in the pancreatic tumor environment.

Preparation and characterization of extracellular vesicles (EVs) loaded with miR-138-5p and pirfenidone (PFD) and subjected to surface modification with integrin α5-targeting peptides (IEVs-PFD/138) and their enhanced cancer-associated fibroblast (CAF)-targeting ability

Fig. 2

a Schematic representation of engineered bone marrow mesenchymal stem cell (BMSC)-derived EVs for the co-delivery of miR-138-5p mimic and PFD to pancreatic CAFs. b Transmission electron microscopy images of EVs (scale bar = 100 nm). c The EV markers (CD9, CD63, Alix, and Tsg101) in both EVs and IEVs were analyzed by Western blotting. d The fluorescence co-localization staining of FAM-peptide (green) and DID-labeled EVs (red). e Nanoparticle tracking analysis (NTA) of EVs and IEVs. f Quantitative real-time polymerase chain reaction (qRT-PCR) of miR-138-5p expression in EVs. Data represent the mean (±SD); n = 3 per group. gh Cellular uptake of DID-labeled EVs and fluorescein amidite (FAM)-miR-138-5p-loaded EVs in CAFs. Laser scanning confocal microscopy (LSCM) (scale bar = 100 μm) and flow cytometric analyses of the uptake of IEVs by CAFs. il Quantification of LSCM and flow cytometric analysis results. Data are presented as mean (±SD); n = 3 per group. m qRT-PCR analysis of miR-138-5p expression in CAFs. Data represent the mean (±SD); n = 3 per group. n In vivo circulation time of IEVs and undecorated EVs. o Analysis of the pancreatic cancer model with in vivo Imaging System (IVIS). Data are presented as mean (±SD); n = 3 per group. p Analysis of the main organs and tumor with in vivo Imaging System (IVIS). Data are presented as mean (±SD); n = 3 per group. q Analysis of the intra-tumoral distribution of IEVs in the tumor section (scale bar = 100 μm). Data are presented as mean (±SD); n = 3 per group

How It Works

  • Targeting and Reprogramming CAFs:
    • The integrin α5-targeting peptides ensure the EVs reach and are taken up by CAFs.
    • Once inside the CAFs, miR-138-5p inhibits the formation of specific protein complexes (FERMT2-TGFBR1 and FERMT2-PYCR1) that are crucial for the activation of the TGF-β signaling pathway and collagen synthesis, respectively. These actions reduce the pro-tumorigenic activities of CAFs.
    • Pirfenidone works alongside miR-138-5p to further suppress fibrosis.
  • Improving Chemotherapy Outcomes:
    • By reprogramming CAFs and reducing fibrosis, the EVs help remodel the TME. This results in decreased tumor pressure, improved drug delivery, reduced tumor hypoxia (low oxygen levels in the tumor), and increased sensitivity of cancer cells to chemotherapy drugs like gemcitabine.

Promising Preclinical Results

The study tested this approach in mouse models that closely mimic human pancreatic cancer. The results were encouraging:

  • The engineered EVs effectively reprogrammed CAFs and remodeled the TME.
  • These changes led to better drug delivery and enhanced the effectiveness of chemotherapy.
  • The overall outcome was a significant reduction in tumor growth.

Conclusion

This innovative strategy of using engineered EVs to target and reprogram CAFs represents a promising therapeutic approach for pancreatic cancer. By modifying the tumor microenvironment, these engineered EVs can improve the effectiveness of existing treatments and offer new hope for patients battling this deadly disease. The success of this approach in preclinical models paves the way for future clinical trials and potential new therapies that could transform the treatment landscape for pancreatic cancer.

Zhou P, Du X, Jia W, Feng K, Zhang Y. (2024) Engineered extracellular vesicles for targeted reprogramming of cancer-associated fibroblasts to potentiate therapy of pancreatic cancer. Signal Transduct Target Ther 9(1):151. [article]

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