SW43-DOX ± loading onto drug-eluting bead, a potential new targeted drug delivery platform for systemic and locoregional cancer treatment - An in vitro evaluation.
SW43-DOX ± loading onto drug-eluting bead, a potential new targeted drug delivery platform for systemic and locoregional cancer treatment - An in vitro evaluation.
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DOI：
10.1016/j.molonc.2016.05.003
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发表时间：
2016-08
影响因子：
6.6
通讯作者：
Kim HS
中科院分区：
文献类型：
--
作者：
Ludwig JM;Gai Y;Sun L;Xiang G;Zeng D;Kim HS
不能切除的原发性癌症及其远处转移的治疗，其中肝脏是最常见的位置之一，仍然受到治疗成功率不足和生存率低的困扰。σ-2受体优先在许多肿瘤细胞上表达，使其成为治疗的有吸引力的靶标。因此，我们开发了一种潜在的靶向药物偶联物，其由Sigma-2受体配体SW 43和多柔比星（SW 43-DOX）组成，用于全身性癌症治疗和局部区域治疗原发性和继发性肝脏恶性肿瘤，当加载到药物洗脱珠（DEB）上时，将其与单独使用多柔比星的治疗进行体外比较。SW 43-D 0X以高亲和力和随后的早期特异性内化特异性结合在肝细胞（Hep G2、Hep 3B）、胰腺（Panc-1）和结肠直肠（HT-29）癌细胞系上表达的σ-2受体。游离SW 43-DOX显示出比单独用阿霉素治疗上级的浓度和时间依赖性癌症毒性。作用机制分析显示，凋亡细胞死亡，增加半胱天冬酶3/7激活和活性氧（ROS）的生产。只有α-生育酚清除ROS，而不是半胱天冬酶抑制剂（Z-VAD-FMK），部分逆转了这种作用。SW 43-DOX可以成功地负载到DEB上，并且与阿霉素相比显示出延长的洗脱动力学。SW 43-DOX负载的DEB相对于阿霉素负载的DEB在所有细胞系中显示出显著更大的时间依赖性毒性。总之，负载到DEB上的新型缀合物SW 43-DOX ±是用于靶向全身和局部癌症治疗的有前景的药物递送平台。
Treatment of unresectable primary cancer and their distant metastases, with the liver representing one of the most frequent location, is still plagued by insufficient treatment success and poor survival rates. The Sigma-2 receptor is preferentially expressed on many tumor cells making it an appealing target for therapy. Thus, we developed a potential targeted drug conjugate consisting of the Sigma-2 receptor ligand SW43 and Doxorubicin (SW43-DOX) for systemic cancer therapy and for locoregional treatment of primary and secondary liver malignancies when loaded onto drug-eluting bead (DEB) which was compared in vitro to the treatment with Doxorubicin alone. SW43-DOX binds specifically to the Sigma-2 receptor expressed on hepatocellular (Hep G2, Hep 3B), pancreatic (Panc-1) and colorectal (HT-29) carcinoma cell lines with high affinity and subsequent early specific internalization. Free SW43-DOX showed superior concentration and time depended cancer toxicity than treatment with Doxorubicin alone. Action mechanisms analysis revealed an apoptotic cell death with increased caspase 3/7 activation and reactive oxygen species (ROS) production. Only ROS scavenging with α-Tocopherol, but not the caspase inhibition (Z-VAD-FMK), partly reverted the effect. SW43-DOX could successfully be loaded onto DEB and showed prolonged eluting kinetics compared to Doxorubicin. SW43-DOX loaded DEB vs. Doxorubicin loaded DEB showed a significantly greater time dependent toxicity in all cell lines. In conclusion, the novel conjugate SW43-DOX ± loading onto DEB is a promising drug delivery platform for targeted systemic and locoregional cancer therapy.