Nano-engineered mesenchymal stem cells (nano-MSCs) are promising targeted drug delivery platforms for treating solid tumors. MSCs engineered with paclitaxel (PTX) loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) are efficacious in treating lung and ovarian tumors in mouse models. The quantitative description of pharmacokinetics (PK) and pharmacodynamics (PD) of nano-MSCs is crucial for optimizing their therapeutic efficacy and clinical translatability. However, successful translation of nano-MSCs is challenging due to their complex composition and physiological mechanisms regulating their pharmacokinetic-pharmacodynamic relationship (PK–PD). Therefore, in this study, a mechanism-based preclinical PK–PD model was developed to characterize the PK–PD relationship of nano-MSCs in orthotopic A549 human lung tumors in SCID Beige mice. The developed model leveraged literature information on diffusivity and permeability of PTX and PLGA NPs, PTX release from PLGA NPs, exocytosis of NPs from MSCs as well as PK and PD profiles of nano-MSCs from previous in vitro and in vivo studies. The developed PK–PD model closely captured the reported tumor growth in animals receiving no treatment, PTX solution, PTX-PLGA NPs and nano-MSCs. Model simulations suggest that increasing the dosage of nano-MSCs and/or reducing the rate of PTX-PLGA NPs exocytosis from MSCs could result in improved anti-tumor efficacy in preclinical settings.

中文翻译：

---

使用纳米工程间充质干细胞的肿瘤靶向药物传递的药代动力学-药效学建模。

纳米工程化的间充质干细胞（nano-MSCs）是用于治疗实体瘤的有希望的靶向药物递送平台。用载有紫杉醇（PTX）的聚（丙交酯-共-乙交酯）（PLGA）纳米颗粒（NP）改造的MSC在小鼠模型中可有效治疗肺部和卵巢肿瘤。纳米MSC的药代动力学（PK）和药效动力学（PD）的定量描述对于优化其治疗效果和临床可翻译性至关重要。但是，由于纳米MSC的复杂组成和调节其药代动力学与药效关系（PK-PD）的生理机制，因此成功地翻译纳米MSC具有挑战性。因此，在这项研究中，建立了基于机制的临床前PK-PD模型，以表征SCID Beige小鼠原位A549人肺肿瘤中纳米MSC的PK-PD关系。开发的模型利用了有关PTX和PLGA NPs的扩散性和渗透性，PLGA NPs中PTX的释放，MSC中NPs的胞吐作用以及以前的体外和体内研究中的纳米MSCs的PK和PD分布的文献信息。发达的PK-PD模型密切记录了未经治疗，PTX溶液，PTX-PLGA NP和纳米MSC的动物的肿瘤生长。模型模拟表明，增加纳米MSC的剂量和/或降低MSC中PTX-PLGA NP胞吐的速率可以提高临床前环境中的抗肿瘤功效。发达的PK-PD模型密切记录了未经治疗，PTX溶液，PTX-PLGA NP和纳米MSC的动物的肿瘤生长。模型模拟表明，增加纳米MSC的剂量和/或降低MSC中PTX-PLGA NP胞吐的速率可以提高临床前环境中的抗肿瘤功效。发达的PK-PD模型密切记录了未经治疗，PTX溶液，PTX-PLGA NP和纳米MSC的动物的肿瘤生长。模型模拟表明，增加纳米MSC的剂量和/或降低MSC中PTX-PLGA NP胞吐的速率可以提高临床前环境中的抗肿瘤功效。