Pharmacokinetic-Pharmacodynamic Modeling of Tumor Targeted Drug Delivery Using Nano-Engineered Mesenchymal Stem Cells.
Pharmacokinetic-Pharmacodynamic Modeling of Tumor Targeted Drug Delivery Using Nano-Engineered Mesenchymal Stem Cells.
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DOI：
10.3390/pharmaceutics13010092
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发表时间：
2021-01-12
期刊：
影响因子：
5.4
通讯作者：
Prabha S
中科院分区：
文献类型：
--
作者：
Cheng S;Nethi SK;Al-Kofahi M;Prabha S
纳米工程间充质干细胞（nano-MSCs）是治疗实体瘤的有希望的靶向药物递送平台。用紫杉醇（PTX）负载的聚（丙交酯-共-乙交酯）（PLGA）纳米颗粒（NP）工程化的MSC在治疗小鼠模型中的肺和卵巢肿瘤中是有效的。纳米间充质干细胞的药代动力学（PK）和药效学（PD）的定量描述对于优化其治疗效果和临床可转化性至关重要。然而，由于其复杂的组成和调节其药代动力学-药效学关系（PK-PD）的生理机制，纳米MSC的成功翻译具有挑战性。因此，在本研究中，开发了一种基于机制的临床前PK-PD模型，以表征纳米MSC在SCID Beige小鼠原位A549人肺肿瘤中的PK-PD关系。所开发的模型利用了关于PTX和PLGA NP的扩散性和渗透性、PTX从PLGA NP的释放、NP从MSC的胞吐以及来自先前体外和体内研究的纳米MSC的PK和PD特征的文献信息。所开发的PK-PD模型紧密地捕获了未接受治疗、PTX溶液、PTX-PLGA NP和纳米MSC的动物中报告的肿瘤生长。模型模拟表明，增加纳米MSC的剂量和/或降低来自MSC的PTX-PLGA NP胞吐的速率可以导致临床前环境中抗肿瘤功效的改善。
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.
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影响因子：
12.4
作者：
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通讯作者：
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影响因子：
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影响因子：
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影响因子：
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