Eljack Sahar, David Stephanie, Chourpa Igor, Faggad Areeg, Allard-Vannier Emilie
EA6295 Nanomédicaments et Nanosondes (NMNS), University of Tours, 37020 Tours, France.
Department of Pharmaceutics, Faculty of Pharmacy, University of Gezira, Wad Medani 21111, Sudan.
Pharmaceuticals (Basel). 2022 Nov 23;15(12):1452. doi: 10.3390/ph15121452.
In this work, lipid-based nanoparticles (LBNP) were designed to combine tyrosine kinase inhibitor (TKI) Lapatinib (LAPA) with siRNA directed against apoptosis inhibitor protein Survivin (siSurvivin) in an injectable form. This nanosystem is based on lipid nanocapsules (LNCs) coated with a cationic polymeric shell composed of chitosan grafted through a transacylation reaction. The hydrophobic LAPA is solubilized in the inner oily core, while hydrophilic siRNA is associated electrostatically onto the nanocarrier’s surface. The co-loaded LBNP showed a narrow size distribution (polydispersity index (PDI) < 0.3), a size of 130 nm, and a slightly positive zeta potential (+21 mV). LAPA and siRNA were loaded in LBNP at a high rate of >90% (10.6 mM) and 100% (4.6 µM), respectively. The siRNA-LAPA_LBNP was readily uptaken by the human epidermal growth factor receptor 2 overexpressed (HER2+) breast cancer cell line SK-BR-3. Moreover, the cytotoxicity studies confirmed that the blank chitosan decorated LBNP is not toxic to the cells with the tested concentrations, which correspond to LAPA concentrations from 1 to 10 µM, at different incubation times up to 96 h. Furthermore, siCtrl.-LAPA_LBNP had a more cytotoxic effect than Lapatinib salt, while siSurvivin-LAPA_LBNP had a significant synergistic cytotoxic effect compared to siCtrl.-LAPA_LBNP. All these findings suggested that the developed modified LBNP could potentiate anti-Survivin siRNA and LAPA anti-cancer activity.
在本研究中，脂质基纳米颗粒（LBNP）被设计成可注射形式，将酪氨酸激酶抑制剂（TKI）拉帕替尼（LAPA）与针对凋亡抑制蛋白生存素的小干扰RNA（siSurvivin）结合。该纳米系统基于脂质纳米囊（LNC），其表面包覆有通过转酰基反应接枝壳聚糖构成的阳离子聚合物壳。疏水性的LAPA溶解在内部油相中，而亲水性的siRNA通过静电作用结合在纳米载体表面。共负载的LBNP呈现出窄尺寸分布（多分散指数（PDI）<0.3），粒径为130 nm，zeta电位略呈正值（+21 mV）。LAPA和siRNA分别以>90%（10.6 mM）和100%（4.6 µM）的高负载率载入LBNP。siRNA-LAPA_LBNP很容易被人表皮生长因子受体2过表达（HER2+）的乳腺癌细胞系SK-BR-3摄取。此外，细胞毒性研究证实，经壳聚糖修饰的空白LBNP在所测试的浓度下对细胞无毒，这些浓度对应于不同孵育时间长达96小时时1至10 µM的LAPA浓度。此外，siCtrl.-LAPA_LBNP比拉帕替尼盐具有更强的细胞毒性作用，而与siCtrl.-LAPA_LBNP相比，siSurvivin-LAPA_LBNP具有显著的协同细胞毒性作用。所有这些发现表明，所开发的改性LBNP可增强抗生存素siRNA和LAPA的抗癌活性。
