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Purpose <p>Pancreatic ductal adenocarcinoma (PDAC) is the most fatal type of pancreatic cancer and has a very low survival rate. DNA methylation plays a significant role in the development and progression of PDAC. Azacitidine (AZA), a potent hypomethylating agent, has shown therapeutic potential for PDAC, but its clinical efficacy is limited due to its rapid in vivo metabolism and degradation.</p> Methods <p>To overcome these limitations associated with AZA, we developed liposomal formulations, encapsulating AZA-copper complex, with improved entrapment and desirable attributes. The resulting liposomes were further tailored with surface modifications, producing polyethylene glycol (PEG) coated liposomes (PEG-Lipo) and CD44 receptor-directed hyaluronic acid-coated liposomes (HA-Lipo). These liposomal formulations were lyophilized using a rationally designed lyophilization process, resulting in stable formulations, which were further confirmed by stability studies.</p> Results <p>The physicochemical characterization showed vesicular structure with a size of &lt; 200&#xa0;nm and optimal drug entrapment (~37–40%). Preclinical pharmacokinetic studies in Wistar rats demonstrated prolonged circulation and increased half-life with surface-coated liposomes as compared to uncoated liposomes (UC-Lipo). In vitro cellular studies using Panc-1 cell lines assessed cytotoxicity, cellular uptake, reactive oxygen species (ROS) generation, and apoptosis. HA-Lipo demonstrated significantly better results (<i>p</i> &lt; 0.0001) than UC-Lipo. Further, in a 3D spheroid model of Panc-1 cells, HA-Lipo showed improved efficacy with spheroid regression (56.32 ± 16.90&#xa0;μm), compared to PEG-Lipo (77.87 ± 41.52&#xa0;μm) and UC-Lipo (136.12 ± 79.99&#xa0;μm).</p> Conclusion <p>These results indicate that HA-Lipo loaded with AZA offers a promising strategy for targeted and effective delivery of AZA to PDAC tissues, potentially improving treatment outcomes.</p> Graphical Abstract <p></p>

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Development and Evaluation of DNA Methyltransferase Inhibitor-Loaded Liposomes as a New Frontier in Pancreatic Ductal Adenocarcinoma Therapy

  • 期刊论文

  • 发表日期：

    2026年1月12日

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  • Sumeet Katke,
  • Sonali Singh,
  • Siddhant Padhi,
  • Kalyani Sakhare,
  • Kumar P Narayan,
  • Akash Chaurasiya

摘要

Purpose

Pancreatic ductal adenocarcinoma (PDAC) is the most fatal type of pancreatic cancer and has a very low survival rate. DNA methylation plays a significant role in the development and progression of PDAC. Azacitidine (AZA), a potent hypomethylating agent, has shown therapeutic potential for PDAC, but its clinical efficacy is limited due to its rapid in vivo metabolism and degradation.

Methods

To overcome these limitations associated with AZA, we developed liposomal formulations, encapsulating AZA-copper complex, with improved entrapment and desirable attributes. The resulting liposomes were further tailored with surface modifications, producing polyethylene glycol (PEG) coated liposomes (PEG-Lipo) and CD44 receptor-directed hyaluronic acid-coated liposomes (HA-Lipo). These liposomal formulations were lyophilized using a rationally designed lyophilization process, resulting in stable formulations, which were further confirmed by stability studies.

Results

The physicochemical characterization showed vesicular structure with a size of < 200 nm and optimal drug entrapment (~37–40%). Preclinical pharmacokinetic studies in Wistar rats demonstrated prolonged circulation and increased half-life with surface-coated liposomes as compared to uncoated liposomes (UC-Lipo). In vitro cellular studies using Panc-1 cell lines assessed cytotoxicity, cellular uptake, reactive oxygen species (ROS) generation, and apoptosis. HA-Lipo demonstrated significantly better results (p < 0.0001) than UC-Lipo. Further, in a 3D spheroid model of Panc-1 cells, HA-Lipo showed improved efficacy with spheroid regression (56.32 ± 16.90 μm), compared to PEG-Lipo (77.87 ± 41.52 μm) and UC-Lipo (136.12 ± 79.99 μm).

Conclusion

These results indicate that HA-Lipo loaded with AZA offers a promising strategy for targeted and effective delivery of AZA to PDAC tissues, potentially improving treatment outcomes.

Graphical Abstract