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<p>To overcome the barriers associated with pancreatic ductal adenocarcinoma (PDAC), primarily due to dense tumor microenvironment (TME), azacitidine (AZA) was incorporated into targeted nanocarriers. We formulated hyaluronic acid (HA)-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) designed to deliver AZA selectively to PDAC cells, taking advantage of the prevalent CD44 receptor overexpression. The NP formulations were prepared using the emulsification-diffusion method and systematically optimized employing a Quality by Design (QbD) methodology. Subsequently, the optimized NP formulations were subjected to a rationally designed lyophilization cycle to enhance physicochemical stability. The resulting NP formulation demonstrated robust stability at 2–8&#xa0;°C for a period of up to three months. In addition, the optimized NPs were subjected to thorough evaluation for their in vivo pharmacokinetic profile using Wistar rat models and in vitro cellular studies. Following I.V. administration of the HA-conjugated AZA-loaded NPs, the C<sub>max</sub> and half-life were found to be 1.82 and 2.73-fold higher than those of the AZA solution. The in vitro cellular uptake, reactive oxygen species (ROS), and apoptosis studies were carried out in the Panc-1 cell line. HA-conjugated AZA-loaded NPs demonstrated significantly (<i>p</i> &lt; 0.0001) better results than the AZA solution. A 3D-spheroidal model was developed using Panc-1 cells, with treatments initiated once spheroids reached a diameter of 300&#xa0;μm. Over 72&#xa0;h of treatment, HA-conjugated AZA-loaded NPs demonstrated increased efficacy by active targeting and induced significantly greater spheroid regression (92.11 ± 29.38&#xa0;μm) compared to unconjugated AZA-loaded nanoparticles (256.86 ± 45.82&#xa0;μm; <i>p</i> &lt; 0.05). The results justify that the HA-conjugated AZA-loaded NPs can be a promising strategy for the effective delivery of AZA for PDAC treatment.</p> Graphical Abstract <p></p>

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Development of DNA Methyltransferase Inhibitor Loaded Surface Engineered Copolymeric Nanoparticles for Pancreatic Ductal Adenocarcinoma Treatment: Optimization, Characterization, and Preclinical Evaluation

  • 期刊论文

  • 发表日期：

    2026年1月16日

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

摘要

To overcome the barriers associated with pancreatic ductal adenocarcinoma (PDAC), primarily due to dense tumor microenvironment (TME), azacitidine (AZA) was incorporated into targeted nanocarriers. We formulated hyaluronic acid (HA)-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) designed to deliver AZA selectively to PDAC cells, taking advantage of the prevalent CD44 receptor overexpression. The NP formulations were prepared using the emulsification-diffusion method and systematically optimized employing a Quality by Design (QbD) methodology. Subsequently, the optimized NP formulations were subjected to a rationally designed lyophilization cycle to enhance physicochemical stability. The resulting NP formulation demonstrated robust stability at 2–8 °C for a period of up to three months. In addition, the optimized NPs were subjected to thorough evaluation for their in vivo pharmacokinetic profile using Wistar rat models and in vitro cellular studies. Following I.V. administration of the HA-conjugated AZA-loaded NPs, the Cmax and half-life were found to be 1.82 and 2.73-fold higher than those of the AZA solution. The in vitro cellular uptake, reactive oxygen species (ROS), and apoptosis studies were carried out in the Panc-1 cell line. HA-conjugated AZA-loaded NPs demonstrated significantly (p < 0.0001) better results than the AZA solution. A 3D-spheroidal model was developed using Panc-1 cells, with treatments initiated once spheroids reached a diameter of 300 μm. Over 72 h of treatment, HA-conjugated AZA-loaded NPs demonstrated increased efficacy by active targeting and induced significantly greater spheroid regression (92.11 ± 29.38 μm) compared to unconjugated AZA-loaded nanoparticles (256.86 ± 45.82 μm; p < 0.05). The results justify that the HA-conjugated AZA-loaded NPs can be a promising strategy for the effective delivery of AZA for PDAC treatment.

Graphical Abstract