PO.ET07.02 · 实验与分子治疗
多次给药后 HCC 小鼠体内 M-CPA/PTX 中紫杉醇与环巴胺的药代动力学/药效学相关性及生物分布
Pharmacokinetic/pharmacodynamic correlation and biodistribution of paclitaxel and cyclopamine from M-CPA/PTX in HCC mice following multiple dosing
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摘要 Abstract
中文摘要
肝细胞癌（HCC）是最常见的肝癌类型，具有高度侵袭性和异质性。由于缺乏有效的诊断技术，HCC 常在手术和化疗干预已不再充分时才被发现。为解决这一问题，我们开发了一种载有微管稳定剂紫杉醇（PTX）和 Hedgehog 通路抑制剂环巴胺（CPA）的聚合物胶束，命名为 M-CPA/PTX。M-CPA/PTX 含 PTX 和 CPA 各 2.5 mg，粒径为 70.6 ± 3.4 nm，PDI 为 0.12 ± 0.04（n = 3），两种药物的包封率均 ≥ 80%。在表达 C-MYC 的转基因小鼠中，以 5 mg/kg M-CPA/PTX 静脉给药后，表征了 PTX 和 CPA 在肿瘤、肝、肺、脾和肾中的生物分布（BD）；小鼠被随机分为四组：溶媒对照组（n = 10）、1 剂组（n = 8）、2 剂组（n = 7）和 3 剂组（n = 9）。统计分析采用方差分析（ANOVA）及 Tukey 事后检验，以 p 值 < 0.05 为显著性标准。BD 数据汇总于表 1。在末次给药后 24 小时，各药物的血液浓度均显著低于肿瘤和器官中的浓度。PTX 与 CPA 的 BD 模式存在明显差异。PTX 浓度在肿瘤中最高，为 369-443 ng/g，其次为肝 >> 肺 > 肾 >> 脾，为 11-15 ng/g。CPA 浓度在肺中较高，为 537-751 ng/g，肾中为 305-339 ng/g，其次为肿瘤，为 218-300 ng/g，肝为 206-328 ng/g。各给药组之间的 BD 水平未见显著改变。基于各只小鼠肿瘤中 PTX 和 CPA 的浓度，建立了与肿瘤生长抑制率（%）的三维 PK/PD 相关性。总之，本研究表征了在 HCC 小鼠模型中多次静脉给药后 PTX 和 CPA 的生物分布，并结合肿瘤中 PTX 和 CPA 的摄取建立了三维 PK/PD 相关性，有望为未来的疗效预测提供依据。表 1：M-CPA/PTX 中 PTX 和 CPA 的生物分布
查看英文原文 English abstract
Hepatocellular Carcinoma (HCC) is the most common form of liver cancer, highly aggressive and heterogenous. Due to lack of effective diagnostic techniques, HCC is often detected when surgical and chemotherapeutic interventions are inadequate. To address this, we developed a polymeric micelle containing Paclitaxel (PTX), a microtubule-stabilizer, and Cyclopamine (CPA), a Hedgehog pathway inhibitor, termed M-CPA/PTX. The M-CPA/PTX contained 2.5 mg each of PTX and CPA, with size of 70.6 ± 3.4 nm, PDI of 0.12 ± 0.04 (n = 3), and encapsulation efficiency of ≥ 80% for both agents. The biodistribution (BD) of PTX and CPA in tumor, liver, lung, spleen and kidney were characterized following IV dosing of 5 mg/kg M-CPA/PTX in C-MYC expressing transgenic mice which were randomized into four groups: vehicle (n = 10), 1 dose (n = 8), 2 doses (n = 7), and 3 doses (n = 9). ANOVA with Tukey's post hoc test was for statistical analysis with p-value < 0.05 for significance. The BD data were compiled in Table 1. The blood concentrations for each agent were substantially lower than those in tumor and organs at 24 hours post the last dose. The BD patterns were distinct between PTX and CPA. The PTX concentrations were the highest in tumor, 369-443 ng/g, followed by liver >> lungs> kidney >> spleen, 11-15 ng/g. The CPA concentrations were high in lungs, 537-751 ng/g, and kidney, 305-339 ng/g, followed by tumor, 218-300 ng/g, and liver, 206-328 ng/g. The BD levels were not significantly altered among the dosing groups. The 3D PK/PD correlation was established for tumor growth inhibition (%), with tumor concentrations of PTX and CPA in individual mice. In conclusion, the biodistributions of PTX and CPA following multiple IV dosing in an HCC mouse model were characterized, and a 3D PK/PD correlation was established with PX and CPA uptakes in tumor, potentially enabling future efficacy projection.Table 1: Biodistribution of PTX and CPA from M-CPA/PTX
利益披露 Disclosure
E. R. Baltrip, None.