本研究旨在使用药代动力学-药效学 (PK-PD) 模型研究体内 pH 响应阿霉素 (DOX) 释放的效果以及叶酸 (FA) 修饰胶束中先导分子的靶向性。使用微透析探针监测 Walker256 荷瘤大鼠瘤内 DOX 浓度的时间曲线，然后进行区室分析，以评估瘤内组织药代动力学。在施用pH响应性DOX释放胶束后350分钟，最大DOX从胶束中释放。然而，FA 对胶束的修饰将药物浓度达到峰值的时间缩短至 150 分钟。此外，FA 修饰导致肿瘤流入速率常数增加 27 倍。随后用 DOX、pH 响应性 DOX 释放胶束和 pH 响应性 DOX 释放 FA 修饰胶束治疗 Walker256 荷瘤大鼠，以监测肿瘤生长时间曲线。将瘤内阈浓度的 DOX（55-64 ng/g 肿瘤）引入药效室构建 PD 模型，然后对肿瘤生长时间曲线进行 PK-PD 分析。所有三种制剂均获得了相似的 DOX 阈值浓度和药物效力结果。随着DOX的药物递送能力的提高，细胞增殖被延迟。使用微透析方法开发的 PK 模型揭示了瘤内 pH 响应的 DOX 分布曲线。这有利于瘤内 PK 参数的估计。具有阈值浓度的 PD 模型有助于估计三种制剂中的 PD 参数，并观察到一致的机制。我们相信我们的 PK-PD 模型可以客观地评估 pH 响应释放能力和先导分子靶向性对药理作用的贡献。

This study aimed to investigate the effect of in vivo pH-responsive doxorubicin (DOX) release and the targetability of pilot molecules in folic acid (FA)-modified micelles using a pharmacokinetic-pharmacodynamic (PK-PD) model. The time profiles of intratumoral DOX concentrations in Walker256 tumor-bearing rats were monitored using a microdialysis probe, followed by compartmental analysis, to evaluate intratumoral tissue pharmacokinetics. Maximal DOX was released from micelles 350 min after the administration of pH-responsive DOX-releasing micelles. However, FA modification of the micelles shortened the time to peak drug concentration to 150 min. Additionally, FA modification resulted in a 27-fold increase in the tumor inflow rate constant. Walker256 tumor-bearing rats were subsequently treated with DOX, pH-responsive DOX-releasing micelles, and pH-responsive DOX-releasing FA-modified micelles to monitor the tumor growth-time profiles. An intratumoral threshold concentration of DOX (55-64 ng/g tumor) was introduced into the drug efficacy compartment to construct a PD model, followed by PK-PD analysis of the tumor growth-time profiles. Similar results of threshold concentration and drug potency of DOX were obtained across all three formulations. Cell proliferation was delayed as the drug delivery ability of DOX was improved. The PK model, which was developed using the microdialysis method, revealed the intratumoral pH-responsive DOX distribution profiles. This facilitated the estimation of intratumoral PK parameters. The PD model with threshold concentrations contributed to the estimation of PD parameters in the three formulations, with consistent mechanisms observed. We believe that our PK-PD model can objectively assess the contributions of pH-responsive release ability and pilot molecule targetability to pharmacological effects.