Kong Chenfan,Sun Jianrong,Hu Xinzi,Li Guangzhi,Wu Song
Immune checkpoint inhibitors (ICIs) are effective agents for tumor immunotherapy. However, their clinical effectiveness is unsatisfactory due to off-target effects and a suppressive immune microenvironment. This study developed a nanodrug delivery system for bladder cancer (BCa) using PCL-MPEG and PCL-PEG-CHO to synthesize internal hydrophobic and external hydrophilic micelles (PP) that encapsulated water-insoluble astragaloside IV (PPA). The aldehyde group on the surface of PPA reacted with the amino group of aPD-L1, allowing the decoration of this antibody on the surface of the micelles. The resultingPPA@aPD-L1effectively piggybacked astragaloside IV and aPD-L1 antibody. These findings suggest that PPA@aPD-L1 is relatively stable in circulation and efficiently binds to BCa cells with the aid of aPD-L1. Additionally, this strategy prolongs the drug’s retention time in tumors. Compared to PBS, PP, and PPA with PPA + aPD-L1 groups, PPA@aPD-L1significantly prolonged the survival of mice with BCa and reduced tumor volume. Mechanistic studies showed that PPA inhibited the NF-κB and STAT3 signaling pathways in tumor cells. Additionally, PPA@aPD-L1increased IFN-γ and decreased IL-10 expression in bladder tumors, affecting the number and type of intratumorally infiltrating T cells. Our study presents a simple and effective drug delivery system that combines herbal monomers with ICIs. It has demonstrated a potent ability to suppress tumor growth and holds potential for future applications.
Background The main challenge of polymeric micelles as drug delivery systems is that the actual delivery efficiency is not as high as expected, which is closely related with the interactions with the complex biological environments such as blood components, phagocytosis, and biodistribution. Herein, we expect to understand these concerns for the clinically relevant micelles that composed of methoxypolyethylene glycol (MPEG) with identical chain length And poly(ε-caprolactone) (PCL) with tunable chain length (PCL n -MPEG) (n=20, 30, and 40) wherein doxorubicin was encapsulated as a model drug. Methods The doxorubicin-loaded PCL n -MPEG micelles were prepared by a dialysis method and characterized by dynamic light scattering and transmission electron microscopy. The surface PEG density and chain conformation were investigated by dissipative particle dynamics simulation. The stability of the micelles was detected by nanoparticle tracking analysis. The effects of PCL chain length on the blood components, phagocytosis, and biodistribution were assayed in vitro and in vivo. Results The micelles exhibited spherical morphology with a diameter about 30nm. The PEG chain conformation from "mushroom-like" to "brush-like" was evident. The micelles have no remarkable effect on the red blood cells, blood coagulation, and platelet activation. Interestingly, the protein adsorption was affected and dependent on the chain conformation, with lowest adsorption for PCL 30 -MPEG, which also has the loWest phagocytosis. The stability of the micelles was in the order of PCL 40 -MPEG>PCL 30 -MPEG>PCL 20 -MPEG which was dependent on the PCL chain length. The micelles mainly accumulated in liver, with the order consistent with their stability, indicating that, besides the phagocytosis, the stability of the micelle plays an important role in biodistribution as well. The related mechanisms were proposed and discussed. Conclusion Manipulating the PEG/PCL ratio of the micelle is an effective approach to modulate the protein adsorption, phagocytosis, and biodistribution, which may be a prerequisite for clinical applications.
危险品化学品经营许可证（带存储）