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Large-Pore Functionalized Mesoporous Silica Nanoparticles as Drug Delivery Vector for a Highly Cytotoxic Hybrid Platinum- Acridine Anticancer Agent

机译:大孔官能化的中孔二氧化硅纳米粒子作为一种高细胞毒性杂交铂 - 吖啶抗癌剂的药物递送载体

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摘要

Large-pore mesoporous silica nanoparticles (MSN) were prepared and functionalized to serve as a highly robust and biocompatible delivery platform for platinum-acridine (PA) anticancer agents. The material showed a high loading capacity for the dicationic, hydrophilic hybrid agent [PtCl(en)(N-[acridin-9-ylaminoethyl]-N-methylpropionamidine)] dinitrate salt (P1A1) and virtually complete retention of payload at neutral pH in a high-chloride buffer. In acidic media mimicking the pH inside the cell lysosomes, rapid, burst-like release of P1A1 from the nanoparticles is observed. Coating of the materials in phospholipid bilayers resulted in nanoparticles with greatly improved colloidal stability. The lipid and carboxylate-modified nanoparticles containing 40 wt% drug caused S-phase arrest and inhibited cell proliferation in pancreatic cancer cells at submicromolar concentrations similar to carrier-free P1A1. The most striking feature of nanoparticle-delivered P1A1 was that the payload did not escape from the acidified lysosomal vesicles into the cytoplasm, but was shuttled to the nuclear membrane and released into the nucleus.
机译:制备大孔隙介孔二氧化硅纳米粒子(MSN),并官能化以作为铂 - 吖啶(PA)抗癌剂的高稳健和生物相容性的递送平台。该材料表现为DICTIXIC,亲水性杂交剂[PTCL(ZH)(N- [吖啶-9-酰基丙烯酰基] -N-甲基丙酰胺)]二硝酸盐(P1A1)的高负载能力,并且在中性pH中几乎完全保留有效载荷高氯化物缓冲液。在模仿细胞溶酶体内的pH的酸性介质中,观察到从纳米颗粒的快速,突破类似P1A1的释放。磷脂双层中的材料涂覆导致纳米颗粒具有极大提高的胶体稳定性。含有40wt%药物的脂质和羧酸盐改性纳米颗粒在类似于载体的P1A1的亚微粒摩尔浓度下引起S相阻滞和抑制细胞增殖在胰腺癌细胞中。纳米粒子交付的P1A1的最引人注目的特征是,有效载荷没有从酸化的溶酶体囊泡中逸出到细胞质中,而是被穿梭于核膜并释放到细胞核中。

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