Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY 14260, USA.
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA.
J Control Release. 2019 Mar 10;297:39-47. doi: 10.1016/j.jconrel.2019.01.030. Epub 2019 Jan 23.
Chemophototherapy (CPT) merges photodynamic therapy with chemotherapy and can substantially enhance drug delivery. Using a singular liposomal formulation for CPT, we describe a semi-mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model to investigate observed antitumor effects. Long-circulating, sterically-stabilized liposomes loaded with doxorubicin (Dox) stably incorporate small amounts of a porphyrin-phospholipid (PoP) photosensitizer in the bilayer. These were administered intravenously to mice bearing low-passage, patient-derived pancreatic cancer xenografts (PDX). Dox PK was described with a two-compartment model and tumor drug disposition kinetics were modeled with first-order influx and efflux rates. Tumor irradiation with 665 nm laser light (200 J/cm) 1 h after liposome administration increased tumor vascular permeabilization and drug accumulation, which was accounted for in the PK/PD model with increased tumor influx and efflux rates by approximately 12- and 4- fold, respectively. This modeling approach provided an overall 7-fold increase in Dox area under the curve in the tumor, matching experimental data (7.4-fold). A signal transduction model based on nonlinear direct cell killing accounted for observed tumor growth patterns. This PK/PD model adequately describes the CPT anti-PDX tumor response based on enhanced drug delivery at the short drug-light interval used.
化学光疗（CPT）将光动力疗法与化学疗法相结合，可以显著增强药物递送。我们使用单一的脂质体制剂进行 CPT，描述了一个半机械的药代动力学-药效学（PK/PD）模型，以研究观察到的抗肿瘤效果。载有阿霉素（Dox）的长循环、空间稳定的脂质体在双层中稳定地掺入少量卟啉磷脂（PoP）光敏剂。这些脂质体被静脉注射到携带低传代、患者来源的胰腺癌异种移植（PDX）的小鼠体内。用两室模型描述 Dox 的 PK，并用一阶流入和流出率来模拟肿瘤药物处置动力学。在脂质体给药后 1 小时用 665nm 激光（200J/cm）照射肿瘤，增加了肿瘤血管通透性和药物积累，这在 PK/PD 模型中通过增加肿瘤流入和流出率来解释，分别增加了约 12 倍和 4 倍。这种建模方法使肿瘤中 Dox 的曲线下面积总体增加了 7 倍，与实验数据（7.4 倍）相匹配。基于非线性直接细胞杀伤的信号转导模型解释了观察到的肿瘤生长模式。该 PK/PD 模型充分描述了基于短药物-光间隔增强药物递送的 CPT 抗 PDX 肿瘤反应。
