Research Centre for Natural Sciences - Eötvös Loránd Research Network, Institute of Materials and Environmental Chemistry, Research Group of Biological Nanochemistry, Magyar tudósok boulevard 2, 1117 Budapest, Hungary.
Research Centre for Natural Sciences - Eötvös Loránd Research Network, Institute of Materials and Environmental Chemistry, Research Group of Biological Nanochemistry, Magyar tudósok boulevard 2, 1117 Budapest, Hungary.
Mater Sci Eng C Mater Biol Appl. 2021 Dec;131:112481. doi: 10.1016/j.msec.2021.112481. Epub 2021 Oct 12.
A sterically stabilized unilamellar nanocarrier vesicle (SSV) system containing dipalmitoylphosphatidylcholine, cholesterol, ursolic acid and PEGylated phospholipid has been developed by exploiting the structural advantages of ursolic acid: by spontaneously attaching to the lipid head groups, it induces curvature at the outer side of the bilayers, allowing the preparation of size-limited vesicles without extrusion. Ursolic acid (UA) also interacts with the PEG chains, supporting steric stabilization even when the amount of PEGylated phospholipid is reduced. Using fluorescence immunohistochemistry, vesicles containing ursolic acid (UA-SSVs) were found to accumulate in the tumor in 3 h on xenografted mouse, suggesting the potential use of these vesicles for passive tumor targeting. Further on, mono- and combination therapy with UA and six different kinase inhibitors (crizotinib, erlotinib, foretinib, gefitinib, refametinib, trametinib) was tested on seven cancer cell-lines. In most combinations synergism was observed, in the case of trametinib even at very low concentration (0.001 μM), which targets the MAPK pathway most often activated in human cancers. The coupled intercalation of UA and trametinib (2:1 molar ratio) into vesicles causes further structural advantageous molecular interactions, promoting the formation of small vesicles. The high drug:lipid molar ratio (~0.5) in the novel type of co-delivery vesicles enables their direct medical application, possibly also overcoming the multidrug resistance effect.
一种具有立体稳定的单层纳米载体囊泡（SSV）系统，含有二棕榈酰磷脂酰胆碱、胆固醇、熊果酸和聚乙二醇化磷脂，通过利用熊果酸的结构优势开发而来：熊果酸通过自发附着在脂质头部基团上，在双层的外侧诱导曲率，允许制备尺寸受限的囊泡而无需挤出。熊果酸（UA）还与 PEG 链相互作用，即使减少聚乙二醇化磷脂的量，也能支持立体稳定。通过荧光免疫组织化学，发现在异种移植小鼠中，含有熊果酸的囊泡（UA-SSVs）在 3 小时内在肿瘤中积累，表明这些囊泡具有被动肿瘤靶向的潜力。进一步，用 UA 和六种不同的激酶抑制剂（克唑替尼、厄洛替尼、福瑞替尼、吉非替尼、refametinib、trametinib）对七种癌细胞系进行了单药和联合治疗。在大多数组合中观察到协同作用，在 trametinib 的情况下，即使在非常低的浓度（0.001 μM）下也是如此，trametinib 靶向的 MAPK 途径在人类癌症中最常被激活。UA 和 trametinib（2:1 摩尔比）偶联插入囊泡中会导致进一步的结构优势分子相互作用，促进小囊泡的形成。新型共递药囊泡中的高药物：脂质摩尔比（~0.5）使其能够直接用于医疗，可能还能克服多药耐药性。
