Laboratory Experimental Oncology and Nanomedicine Innovation Center Erasmus (NICE), Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
Boston Scientific, Marlborough, MA, USA.
Commun Biol. 2021 Jul 28;4(1):920. doi: 10.1038/s42003-021-02428-z.
Intravascular triggered drug delivery systems (IV-DDS) for local drug delivery include various stimuli-responsive nanoparticles that release the associated agent in response to internal (e.g., pH, enzymes) or external stimuli (e.g., temperature, light, ultrasound, electromagnetic fields, X-rays). We developed a computational model to simulate IV-DDS drug delivery, for which we quantified all model parameters in vivo in rodent tumors. The model was validated via quantitative intravital microscopy studies with unencapsulated fluorescent dye, and with two formulations of temperature-sensitive liposomes (slow, and fast release) encapsulating a fluorescent dye as example IV-DDS. Tumor intra- and extravascular dye concentration dynamics were extracted from the intravital microscopy data by quantitative image processing, and were compared to computer model results. Via this computer model we explain IV-DDS delivery kinetics and identify parameters of IV-DDS, of drug, and of target tissue for optimal delivery. Two parameter ratios were identified that exclusively dictate how much drug can be delivered with IV-DDS, indicating the importance of IV-DDS with fast drug release (~sec) and choice of a drug with rapid tissue uptake (i.e., high first-pass extraction fraction). The computational model thus enables engineering of improved future IV-DDS based on tissue parameters that can be quantified by imaging.
用于局部药物递送的血管内触发药物递送系统（IV-DDS）包括各种对内部（例如 pH 值、酶）或外部刺激（例如温度、光、超声、电磁场、X 射线）有响应的刺激响应性纳米颗粒，以释放相关药物。我们开发了一种计算模型来模拟 IV-DDS 药物递送，为此我们在啮齿动物肿瘤中体内量化了所有模型参数。该模型通过使用未封装的荧光染料进行定量活体显微镜研究以及使用封装荧光染料的两种温度敏感脂质体（缓慢和快速释放）制剂进行验证，作为示例 IV-DDS。通过定量图像处理从活体显微镜数据中提取肿瘤内和血管外染料浓度动力学，并将其与计算机模型结果进行比较。通过该计算机模型，我们解释了 IV-DDS 递送动力学，并确定了 IV-DDS、药物和靶组织的参数，以实现最佳递送。确定了两个参数比，这些参数比专门决定了可以通过 IV-DDS 递送多少药物，这表明具有快速药物释放（~秒）的 IV-DDS 和选择具有快速组织摄取（即高首过提取分数）的药物的重要性。因此，该计算模型能够根据可以通过成像定量的组织参数来设计改进的未来 IV-DDS。
