Novel Pancreatic Cancer Therapy Targeting Cell Surface Glycans by Liposomes Modified with rBC2LCN Lectin
Novel Pancreatic Cancer Therapy Targeting Cell Surface Glycans by Liposomes Modified with rBC2LCN Lectin
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DOI：
10.1159/000513430
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发表时间：
2021-01
影响因子：
1.6
通讯作者：
Sota Kimura;T. Oda;Osamu Shimomura;Tsuyoshi Enomoto;S. Hashimoto;Yukihito Kuroda;Yang Yu-;Ko Kurimori;Tomoaki Furuta;Yoshihiro Miyazaki;H. Tateno
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作者：
Sota Kimura;T. Oda;Osamu Shimomura;Tsuyoshi Enomoto;S. Hashimoto;Yukihito Kuroda;Yang Yu-;Ko Kurimori;Tomoaki Furuta;Yoshihiro Miyazaki;H. Tateno
前言：由于癌细胞的最外层覆盖着各种多糖，针对这些群体可能成为癌症治疗的有效策略。我们以前报道过岩藻糖化的多糖在胰腺癌细胞上特异表达，并且与这些多糖特异结合的蛋白质，即rBC2LCN凝集素，是一种潜在的导向药物载体。在本研究中，通过用rBC2LCN凝集素修饰阿霉素脂质体表面，制备了一种新型的糖靶向纳米颗粒。该制剂的有效性和特异性被称为Lec-Doxosome，在人体胰腺癌模型中进行了体外和体内的检测。方法：通过脂质连接物将rBC2LCN凝集素插入脂质体表面，采用后插入法制备LEC-Doxosome。将Lec-Doxosome应用于与rBC2LCN凝集素有亲和力的人胰腺癌细胞株(Capan-1)，比较了Lec-Doxosome与未修饰脂质体的细胞结合、摄取和细胞毒性。在体内试验中，Lec-Doxosome每周静脉注射一次，共3周，注射到荷有皮下肿瘤的小鼠体内。结果：体外应用Lec-Doxosome后，阿霉素在细胞内的蓄积量是未修饰脂质体的1.2~1.6倍，细胞毒性是未修饰脂质体的1.5倍。在体内，Lec-Doxosome的平均肿瘤重量(368毫克)比未经修饰的脂质体治疗的小鼠(456毫克)要低，没有引起任何额外的不良反应。结论：rBC2LCN凝集素是一种有效的修饰剂，可提高纳米粒靶向肿瘤细胞表面糖链的效率。
Introduction: Since the outermost layer of cancer cells is covered with various glycans, targeting these groups may serve as an effective strategy in cancer therapy. We previously reported that fucosylated glycans are specifically expressed on pancreatic cancer cells, and that a protein specifically binding to these glycans, namely rBC2LCN lectin, is a potential guiding drug carrier. In the present study, a novel type of glycan-targeting nanoparticle was developed by modifying the surface of doxorubicin-containing liposomes with rBC2LCN lectin. The efficiency and specificity of this formulation, termed Lec-Doxosome, were examined in vitro and in vivo in human pancreatic cancer models. Methods: Lec-Doxosome was prepared by a post-insertion method based on the insertion of rBC2LCN lectin into the liposomal surface via a lipid linker. The in vitro cellular binding, uptake, and cytotoxicity of Lec-Doxosome were compared with the corresponding parameters in the unmodified liposomes by applying to human pancreatic cancer cell line (Capan-1) with affinity for rBC2LCN lectin. For the in vivo assay, Lec-Doxosome was intravenously injected once per week for a total of 3 weeks into mice bearing subcutaneous tumors. Results: The in vitro application of Lec-Doxosome resulted in a 1.2- to 1.6-fold higher intracellular doxorubicin accumulation and a 1.5-fold stronger cytotoxicity compared with the respective rates of accumulation and cytotoxicity in the unmodified liposomes. In vivo, Lec-Doxosome reduced the mean tumor weight (368 mg) compared with that in mice treated with unmodified liposomes (456 mg), without causing any additional adverse events. Conclusion: It was demonstrated from the results obtained herein that rBC2LCN lectin is a potent modifier, as a means for boosting the efficiency of nanoparticles in the targeting of cancer cell surface glycans.