Abstract：
Various chemotherapeutic agents are used to treat breast cancer (BC); one of them is the anthracycline antibiotic doxorubicin (Dox), which, in addition to its cytostatic effect, has serious side effects. In order to reduce its negative impact on healthy organs and tissues and to increase its accumulation in tumors, Dox was incorporated into phospholipid nanoparticles. The additional use of vector molecules for targeted delivery to specific targets can increase the effectiveness of Dox due to higher accumulation of the active substance in the tumor tissue. The integrin αvβ3, which plays an important role in cancer angiogenesis, and the folic acid receptor, which is responsible for cell differentiation and proliferation, have been considered in this study as targets for such vector molecules. Thus, a phospholipid composition of Dox containing two vector ligands, cRGD peptide and folic acid (NPh-Dox-cRGD-Fol(3,4)), was prepared. Study of the physical properties of the developed composition NPh-Dox-cRGD-Fol(3,4) showed that the average particle size was 39.62±4.61 nm, the ζ-potential value was 4.17±0.83 mV. Almost all Dox molecules were incorporated into phospholipid nanoparticles (99.85±0.21%). The simultaneous use of two vectors in the composition led to an increase in the Dox accumulation in MDA-MB-231 BC cells by almost 20% as compared to compositions containing each vector separately (folic acid or the cRGD peptide). Moreover, the degree of Dox internalization was 22% and 24% higher than in the case of separate use of folic acid and cRGD peptide, respectively. The cytotoxic effect on MDA-MB-231 cells was higher during incubations with the compositions containing folic acid as a single vector (NPh-Dox-Fol(3,4)) and together with the RGD peptide (NPh-Dox-cRGD-Fol(3,4)). Experiments on the Wi-38 diploid fibroblast cell line have shown a significantly lower degree of cytotoxic effect of the phospholipid composition, regardless of the presence of the vector molecules in it, as compared to free Dox. The results obtained indicate the potential of using two vectors in one phospholipid composition for targeted delivery of Dox.
摘要：
各种化学治疗剂用于治疗乳腺癌（BC）；其中之一是蒽环类抗生素阿霉素（Dox），which,除了它的细胞抑制作用，有严重的副作用。为了减少其对健康器官和组织的负面影响，并增加其在肿瘤中的积累，将Dox掺入磷脂纳米颗粒中。用于靶向递送至特定靶标的载体分子的额外使用可由于活性物质在肿瘤组织中的更高积累而增加Dox的有效性。整合素αvβ3在肿瘤血管生成中起重要作用,叶酸受体，负责细胞分化和增殖，在这项研究中已被认为是此类载体分子的靶标。因此，含有两个载体配体的Dox磷脂组合物，cRGD肽和叶酸（NPh-Dox-cRGD-Fol（3,4）），准备好了。对开发的组合物NPh-Dox-cRGD-Fol（3,4）的物理性质的研究表明，平均粒径为39.62±4.61nm，ζ电位值为4.17±0.83mV。几乎所有的Dox分子都掺入到磷脂纳米颗粒中(99.85±0.21%)。与分别含有每种载体的组合物(叶酸或cRGD肽)相比,在组合物中同时使用两种载体导致MDA-MB-231BC细胞中Dox积累增加几乎20%。此外，Dox内化程度比单独使用叶酸和cRGD肽的情况高22％和24％，分别。在用含有叶酸作为单一载体的组合物(NPh-Dox-Fol(3,4))和RGD肽(NPh-Dox-cRGD-Fol(3,4))孵育期间,对MDA-MB-231细胞的细胞毒性作用更高。Wi-38二倍体成纤维细胞系的实验表明，磷脂成分的细胞毒性作用程度明显较低，不管载体分子的存在，与免费的Dox相比。获得的结果表明在一种磷脂组合物中使用两种载体用于靶向递送Dox的潜力。
