Department of Surgery, Clinical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Department of Surgery, Clinical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan,
Eur Surg Res. 2020;61(4-5):113-122. doi: 10.1159/000513430. Epub 2021 Jan 27.
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.
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.
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.
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.
由于癌细胞的最外层覆盖着各种糖链，因此针对这些糖链可能成为癌症治疗的有效策略。我们之前报道过，岩藻糖化聚糖特异性表达于胰腺癌细胞上，并且能够特异性结合这些聚糖的蛋白质，即 rBC2LCN 凝集素，是一种有潜力的导向药物载体。在本研究中，我们通过用 rBC2LCN 凝集素修饰载有阿霉素的脂质体的表面，开发了一种新型的糖靶向纳米颗粒。在体外和体内人胰腺癌细胞模型中，我们研究了这种名为 Lec-Doxosome 的制剂的效率和特异性。
通过基于脂质连接子将 rBC2LCN 凝集素插入脂质体表面的后插入方法制备 Lec-Doxosome。通过应用于具有 rBC2LCN 凝集素亲和力的人胰腺癌细胞系（Capan-1），比较 Lec-Doxosome 的体外细胞结合、摄取和细胞毒性与未修饰脂质体的相应参数。对于体内试验，Lec-Doxosome 每周静脉内注射一次，共 3 周，注射到皮下肿瘤小鼠中。
与未修饰脂质体的积累率和细胞毒性相比，Lec-Doxosome 的体外应用导致细胞内阿霉素的积累增加了 1.2-1.6 倍，细胞毒性增强了 1.5 倍。在体内，与用未修饰脂质体治疗的小鼠相比，Lec-Doxosome 降低了平均肿瘤重量（368mg），而没有引起任何其他不良反应。
从本文获得的结果表明，rBC2LCN 凝集素是一种有效的修饰剂，可提高纳米颗粒靶向癌细胞表面糖链的效率。
