Quantitative modeling of the dynamics and intracellular trafficking of far-red light-activatable prodrugs: implications in stimuli-responsive drug delivery system.
Quantitative modeling of the dynamics and intracellular trafficking of far-red light-activatable prodrugs: implications in stimuli-responsive drug delivery system.
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DOI：
10.1007/s10928-017-9543-z
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发表时间：
2017-12
影响因子：
2.5
通讯作者：
Woo S
中科院分区：
文献类型：
--
作者：
Li M;Thapa P;Rajaputra P;Bio M;Peer CJ;Figg WD;You Y;Woo S
光动力疗法（PDT）与抗肿瘤药物的组合是治疗局部癌症的补充策略。我们开发了一种独特的光敏剂（PS）缀合的紫杉醇（PTX）前药，其中PS被近红外波长的光激发以位点特异性地释放PTX，同时产生单线态氧（SO），从而用PTX和SO有效地杀死癌细胞。本研究的目的是确定影响这种光活化前药的联合疗效的决定因素，特别是释放的PTX的旁观者杀伤效应。使用PS-共轭PTX作为模型系统，我们开发了一个定量的数学模型描述的细胞内运输。使用体外人癌细胞的实验数据验证了前药的动力学和模型预测。敏感性分析表明，与释放的PTX的细胞外浓度、前药摄取、靶标接合和靶标丰度相关的参数在确定前药的组合杀伤功效中是关键的。我们发现释放的PTX细胞毒性对药物在细胞外空间的保留时间最敏感。调节药物内化和缀合靶向丰富的受体的药物可能提供一种新的策略，以最大限度地提高远红光激活的前药系统的杀伤能力。这些结果为PDT组合体内研究的设计提供了指导，并对其他刺激响应性药物递送系统具有影响。
The combination of photodynamic therapy (PDT) with anti-tumor agents is a complimentary strategy to treat local cancers. We developed a unique photosensitizer (PS)-conjugated paclitaxel (PTX) prodrug in which a PS is excited by near-infrared wavelength light to site-specifically release PTX while generating singlet oxygen (SO) to effectively kill cancer cells with both PTX and SO. The aim of the present study was to identify the determinants influencing the combined efficacy of this light-activatable prodrug, especially the bystander killing effects from released PTX. Using PS-conjugated PTX as a model system, we developed a quantitative mathematical model describing the intracellular trafficking. Dynamics of the prodrug and the model predictions were verified with experimental data using human cancer cells in vitro. The sensitivity analysis suggested that parameters related to extracellular concentration of released PTX, prodrug uptake, target engagement, and target abundance are critical in determining the combined killing efficacy of the prodrug. We found that released PTX cytotoxicity was most sensitive to the retention time of the drug in extracellular space. Modulating drug internalization and conjugating the agents targeted to abundant receptors may provide a new strategy for maximizing the killing capacity of the far-red light-activatable prodrug system. These results provide guidance for the design of the PDT combination study in vivo and have implications for other stimuli-responsive drug delivery systems.
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影响因子：
16.1
作者：
Deelman, Leo E.;Decleves, Anne-Emilie;Rychak, Joshua J.;Sharma, Kumar
通讯作者：
Sharma, Kumar
影响因子：
16.1
作者：
Au JL;Yeung BZ;Wientjes MG;Lu Z;Wientjes MG
通讯作者：
Wientjes MG
影响因子：
8
作者：
Fröhlich E
通讯作者：
Fröhlich E
远红色的光线可激活，多功能前药，用于荧光光学成像和组合处理。
影响因子：
7.3
作者：
Bio M;Rajaputra P;Nkepang G;You Y
通讯作者：
You Y
影响因子：
2.9
作者：
JUSKO, WJ
通讯作者：
JUSKO, WJ