多功能熊果酸与激酶抑制剂联合用于抗癌药物载体囊泡

IF 8.1 1区 工程技术 Q1 MATERIALS SCIENCE, BIOMATERIALS Materials science & engineering. C, Materials for biological applications Pub Date : 2021-12-01 DOI:10.1016/j.msec.2021.112481
A. Lőrincz , J. Mihály , A. Wacha , Cs. Németh , B. Besztercei , P. Gyulavári , Z. Varga , I. Peták , A. Bóta
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引用次数: 4

摘要

利用熊果酸的结构优势,开发了一种含有双棕榈酰磷脂酰胆碱、胆固醇、熊果酸和聚乙二醇化磷脂的空间稳定单层纳米载体囊泡(SSV)系统:通过自发地附着在脂质头基团上,它在双层结构的外侧诱导曲率,允许制备尺寸有限的囊泡而无需挤压。熊果酸(UA)也与PEG链相互作用,即使在聚乙二醇化磷脂的量减少时也支持空间稳定。利用荧光免疫组化技术,发现含有熊果酸(uv - ssv)的囊泡在异种移植小鼠的肿瘤中蓄积3小时,提示这些囊泡可能用于被动靶向肿瘤。进一步,UA和六种不同的激酶抑制剂(克唑替尼、厄洛替尼、福替尼、吉非替尼、瑞法替尼、曲美替尼)的单一和联合治疗在7种癌细胞系上进行了测试。在大多数组合中,即使在极低浓度(0.001 μM)的情况下,曲美替尼也观察到协同作用,它靶向人类癌症中最常激活的MAPK途径。UA和曲美替尼(2:1摩尔比)耦合嵌入到囊泡中,进一步引起结构上有利的分子相互作用,促进小囊泡的形成。新型共递送囊泡的高药脂摩尔比(~0.5)使其能够直接应用于医学,也可能克服多药耐药效应。
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Combination of multifunctional ursolic acid with kinase inhibitors for anti-cancer drug carrier vesicles

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.

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来源期刊
CiteScore
12.60
自引率
0.00%
发文量
28
审稿时长
3.3 months
期刊介绍: Materials Today is a community committed to fostering the creation and sharing of knowledge and experience in materials science. With the support of Elsevier, this community publishes high-impact peer-reviewed journals, organizes academic conferences, and conducts educational webinars, among other initiatives. It serves as a hub for advancing materials science and facilitating collaboration within the scientific community.
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