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Objective <p>This study aimed to design and optimize anti-PD-L1 peptide-conjugated mocetinostat prodrug nanoparticles (PD-NPs) as a targeted chemoimmunotherapeutic strategy.</p> Method <p>Rationale design and bioinformatic analysis were performed to determine the binding affinity of PD-NPs with targeted proteins through molecular docking and molecular dynamic simulation. PD-NPs were synthesized by self-assembling EDC/NHS coupling reaction, characterized by different spectroscopical techniques. Enzyme-responsive drug release was assessed through <i>in-vitro</i> drug release study in presence and absence of cathepsin B, and quantified by HPLC and UV–visible spectroscopy. <i>In-vitro</i> studies were performed in A549, NCI-H1975 and NCI-H460 cells to assess HDAC activity, PD-1/PD-L1 binding affinity, intracellular cathepsin B levels, and immune activation. <i>In-vivo</i> toxicity study, hemolysis and pharmacokinetic study were performed to evaluate biological safety profile. Biodistribution, and histopathological evaluations were performed in B16-F10-induced lung tumor-bearing mice to assess therapeutic efficacy of PD-NPs.</p> Result <p>The optimized zeta potential value was + 23.26&#xa0;mV and Polydispersity Index (PDI) 0.21, indicating colloidal stability. TEM analysis demonstrated that PD-NPs has uniform spherical morphology. High drug loading efficiency was estimated to be 83.23 ± 2.5% which include 50.49% of anti-PD-L1 peptide and 32.74% of mocetinostat within the PD-NPs. CD spectroscopy, and DNA intercalation assay confirmed cathepsin B-triggered drug release. <i>In-vitro</i> studies demonstrated PD-NPs significantly exhibited HDAC enzymatic inhibition, PD-1/PD-L1 interaction blockade, and immune activation. <i>In-vivo</i> studies represented PD-NPs efficiently improving hemocompatibility, prolonging systemic circulation, enhancing tumor specific accumulation, and restoring typical architecture of lung tissues.</p> Conclusion <p>PD-NPs showed remarkable structural stability, enzyme-responsive activation, and favorable biocompatibility, indicating their potential as a predictive cancer chemoimmunotherapy.</p> Graphical Abstract <p></p>

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Rational Design, Optimization and Bioinformatic Analysis of Anti-PD-L1 Peptide Conjugated Mocetinostat Prodrug Nanoparticles for Predictive Cancer Chemoimmunotherapeutic Efficacy

  • 期刊论文

  • 发表日期：

    2026年5月27日

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  • Sakuntala Gayen,
  • Ishita Sanyal,
  • Souvik Roy

摘要

Objective

This study aimed to design and optimize anti-PD-L1 peptide-conjugated mocetinostat prodrug nanoparticles (PD-NPs) as a targeted chemoimmunotherapeutic strategy.

Method

Rationale design and bioinformatic analysis were performed to determine the binding affinity of PD-NPs with targeted proteins through molecular docking and molecular dynamic simulation. PD-NPs were synthesized by self-assembling EDC/NHS coupling reaction, characterized by different spectroscopical techniques. Enzyme-responsive drug release was assessed through in-vitro drug release study in presence and absence of cathepsin B, and quantified by HPLC and UV–visible spectroscopy. In-vitro studies were performed in A549, NCI-H1975 and NCI-H460 cells to assess HDAC activity, PD-1/PD-L1 binding affinity, intracellular cathepsin B levels, and immune activation. In-vivo toxicity study, hemolysis and pharmacokinetic study were performed to evaluate biological safety profile. Biodistribution, and histopathological evaluations were performed in B16-F10-induced lung tumor-bearing mice to assess therapeutic efficacy of PD-NPs.

Result

The optimized zeta potential value was + 23.26 mV and Polydispersity Index (PDI) 0.21, indicating colloidal stability. TEM analysis demonstrated that PD-NPs has uniform spherical morphology. High drug loading efficiency was estimated to be 83.23 ± 2.5% which include 50.49% of anti-PD-L1 peptide and 32.74% of mocetinostat within the PD-NPs. CD spectroscopy, and DNA intercalation assay confirmed cathepsin B-triggered drug release. In-vitro studies demonstrated PD-NPs significantly exhibited HDAC enzymatic inhibition, PD-1/PD-L1 interaction blockade, and immune activation. In-vivo studies represented PD-NPs efficiently improving hemocompatibility, prolonging systemic circulation, enhancing tumor specific accumulation, and restoring typical architecture of lung tissues.

Conclusion

PD-NPs showed remarkable structural stability, enzyme-responsive activation, and favorable biocompatibility, indicating their potential as a predictive cancer chemoimmunotherapy.

Graphical Abstract