Superior Penetration and Cytotoxicity of HPMA Copolymer Conjugates of Pirarubicin in Tumor Cell Spheroid
Superior Penetration and Cytotoxicity of HPMA Copolymer Conjugates of Pirarubicin in Tumor Cell Spheroid
复制标题
DOI：
10.1021/acs.molpharmaceut.9b00248
复制
发表时间：
2019-08-01
影响因子：
4.9
通讯作者：
Maeda, Hiroshi
中科院分区：
文献类型：
--
作者：
Nakamura, Hideaki;Koziolova, Eva;Maeda, Hiroshi
吡柔比素（THP）的N-（2-羟丙基）甲基丙烯酰胺共聚物缀合物P-THP通过增强渗透性和滞留性（EPR）效应在实体肿瘤组织中选择性积累。尽管大分子抗肿瘤药物在实体肿瘤中有较高的蓄积，但由于肿瘤组织扩散差以及肿瘤血流受阻，一些大分子抗肿瘤药物的治疗效果不佳。在此，我们证实在体外1-4小时的培养时间内，细胞对P-THP的摄取比游离THP少25倍。P-THP通过融合紧密的单层细胞连接处的传代率是游离THP的12倍，在4小时内，P-THP进入肿瘤细胞球状体的深度是游离THP的1.3-1.7倍。此外，P-THP对球形肿瘤细胞的细胞毒性与游离THP相当，但在体外对单层细胞的细胞毒性比游离THP低7倍。这些结果表明，与游离的THP相比，P-THP在肿瘤细胞球体内的扩散更深。因此，在体内，P-THP比游离THP表现出更有效的抗肿瘤活性，这也得到了P-THP比游离THP更好的药代动力学和肿瘤积累的支持。
N-(2-Hydroxypropyl)methacrylamide copolymer conjugates of pirarubicin (THP), P-THP, accumulates selectively in solid tumor tissue by the enhanced permeability and retention (EPR) effect. Despite of high accumulation in solid tumors, some macromolecular antitumor agents show poor therapeutic outcome because of poor tissue diffusion into the tumor as well as obstructed tumor blood flow. Here, we confirmed that cellular uptake of P-THP was 25 times less than that of free THP at 1-4 h incubation time in vitro. The passage of P-THP through the confluent tight-monolayer cells junction was 12 times higher than free THP, and P-THP penetrated deeper into the tumor cell spheroid (1.3-1.7-fold) than free THP in 4 h. In addition, P-THP showed cytotoxicity comparable to that of free THP to tumor-cells in spheroid form, despite of 7 times lower cytotoxicity of P-THP to the monolayer cells to that of free THP in vitro. These results indicate that P-THP administration can exhibit deeper diffusion into the tumor cell spheroid than free THP. As a consequence, P-THP exhibits more efficient antitumor activity than free THP in vivo, which is also supported by better pharmacokinetics and tumor accumulation of P-THP than free THP.