In contrast to plasma pharmacokinetics, intratumoral pharmacokinetics of doxorubicin (DOX) determines its spatial anti-tumoral activity. Three-dimensional multicellular layers (MCL) model for solid tumors present optimum experimental platform for studying the intratumoral pharmacokinetics of DOX. This might imply new insights for understanding intratumoral pharmacokinetic parameters with realistic clinical implications. Herein, we are presenting simplified method for the spatial in-situ concentration assessment of DOX within the avascular simulating MCL solid tumor model of DLD-1 and HT-29 cell lines. DLD-1 and HT-29 formed viable well-structured MCL model abundant in extracellular matrix component (fibronectin). DOX (100 µM) showed stronger anti-proliferative effect against MCL of DLD-1 compared to HT-29 MCL (38.8% and 27.9%, respectively). The differential potencies of DOX closely correlate to the intratumoral pharmacokinetics within MCL’s of both cell lines. DOX penetrated faster and washed out slower through the MCL of DLD-1 compared to HT-29 MCL. Distribution of DOX within MCL of DLD-1 was more homogenous compared to HT-29 MCL. Tissue concentration of DOX within MCL of DLD-1 was significantly higher than HT-29 MCL’s after 96 h exposure (0.7 and 0.4 µmole/gm tissue, respectively). Concentration of DOX within MCL of both cell lines exceeded the IC₅₀ under monolayer conditions (2.3 ± 0.6 µM and 0.6 ± 0.1 µM, respectively). In addition, DOX was extensively metabolized to less active metabolites (doxorubicinol and doxorubicinone) through the thickness of both MCL’s. In conclusion, Intratumoral pharmacokinetic barriers to DOX might be key determinant in drug resistance on the tissue level, despite cellular and molecular events.

与血浆药代动力学相反，阿霉素（DOX）的肿瘤内药代动力学决定了其空间抗肿瘤活性。实体瘤的三维多细胞层（MCL）模型为研究DOX的瘤内药代动力学提供了最佳的实验平台。这可能意味着了解具有实际临床意义的肿瘤内药代动力学参数的新见解。在此，我们提出了一种用于空间原位的简化方法DLD-1和HT-29细胞系模拟MCL实体血管模型中DOX的浓度评估 DLD-1和HT-29形成了可行的结构良好的MCL模型，该模型富含细胞外基质成分（纤连蛋白）。DOX（100 µM）与HT-29 MCL（分别为38.8％和27.9％）相比，对DLD-1的MCL具有更强的抗增殖作用。DOX的差异效力与两种细胞系的MCL内的肿瘤内药代动力学密切相关。与HT-29 MCL相比，DOX通过DLD-1的MCL渗透更快，洗出速度更慢。与HT-29 MCL相比，DOX在DLD-1的MCL中的分布更均匀。暴露96小时后，DLD-1的MCL中DOX的组织浓度显着高于HT-29 MCL（分别为0.7和0.4 µmol / gm组织）。₅₀在单层条件下（分别为2.3±0.6 µM和0.6±0.1 µM）。此外，DOX通过两个MCL的厚度被广泛代谢为活性较低的代谢物（阿霉素和阿霉素）。总之，尽管有细胞和分子事件，DOX的瘤内药代动力学障碍可能是决定组织水平耐药性的关键因素。