Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, M5S 3M2, Canada.
Drug Deliv Transl Res. 2015 Feb;5(1):15-26. doi: 10.1007/s13346-014-0210-2.
αvβ3 integrin receptors expressed on cancer cell surfaces play a crucial role in promoting tumor angiogenesis and cancer cell metastasis. Thus, cyclic arginyl-glycyl-aspartic acid (cRGD) peptides have been explored as a αvβ3 integrin receptor-specific targeting moiety for the targeted delivery of nanoparticle-loaded therapeutics. However, our previous study showed that cyclic RGD could act as a double-edged sword that, on one hand, extended the retention of cRGD-modified solid lipid nanoparticles (RGD-SLNs) at αvβ3 integrin receptor overexpressing breast carcinoma, and yet on the other hand, decreased the amount of tumor accumulation of RGD-SLNs attributable to the greater uptake by the mononuclear phagocyte system (MPS). Therefore, we aimed to optimize the RGD-decorated nanoparticle systems for (1) inhibiting αvβ3 integrin receptor overexpressing tumor cell metastasis and (2) increasing nanoparticle accumulation to tumor site. SLNs with cRGD content ranging from 0 to 10 % mol of total polyethyleneglycol (PEG) chains were synthesized. The binding of RGD-SLNs with αvβ3 integrin receptors increased with increasing cRGD concentration on the nanoparticles. RGD-SLNs were demonstrated to inhibit MDA-MB-231 cell adhesion to fibronectin and invasion through Matrigel. In vivo whole-body fluorescence imaging revealed that 1 % cRGD on the SLNs' surface had maximum tumor accumulation with extended tumor retention among all formulations tested in an orthotopic MDA-MB-231/EGFP breast tumor model. This work has laid a foundation for further development of anticancer drug-loaded optimized cRGD nanoparticle formulations for the treatment of breast cancer metastasis.
αvβ3 整联蛋白受体在癌细胞表面表达，在促进肿瘤血管生成和癌细胞转移中起着关键作用。因此，环精氨酸-甘氨酸-天冬氨酸（cRGD）肽已被探索作为αvβ3 整联蛋白受体特异性靶向部分，用于载药纳米颗粒的靶向递药。然而，我们之前的研究表明，环 RGD 可以起到双刃剑的作用，一方面，延长了 cRGD 修饰的固体脂质纳米粒（RGD-SLNs）在过表达αvβ3 整联蛋白受体的乳腺癌中的保留时间，另一方面，由于单核吞噬细胞系统（MPS）的摄取量增加，减少了 RGD-SLNs 的肿瘤积累量。因此，我们旨在优化 RGD 修饰的纳米颗粒系统，（1）抑制过表达αvβ3 整联蛋白受体的肿瘤细胞转移，（2）增加纳米颗粒在肿瘤部位的积累。合成了 cRGD 含量为总聚乙二醇（PEG）链的 0 至 10%摩尔的 SLNs。RGD-SLNs 与αvβ3 整联蛋白受体的结合随着纳米粒上 cRGD 浓度的增加而增加。RGD-SLNs 被证明可以抑制 MDA-MB-231 细胞与纤连蛋白的黏附和通过 Matrigel 的侵袭。体内全身荧光成像显示，在原位 MDA-MB-231/EGFP 乳腺癌模型中，所有测试制剂中，表面有 1% cRGD 的 SLNs 具有最大的肿瘤积累量，并延长了肿瘤保留时间。这项工作为进一步开发用于治疗乳腺癌转移的载药优化 cRGD 纳米颗粒制剂奠定了基础。
