Laboratory for Targeted Drug Delivery and Personalized Medicine Technologies, Department of Chemical Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel; Russell Berrie Nanotechnology Institute, The Norman Seiden Multidisciplinary Graduate program, Technion-Israel Institute of Technology, Haifa 3200, Israel.
Laboratory for Targeted Drug Delivery and Personalized Medicine Technologies, Department of Chemical Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel.
J Control Release. 2019 Aug 10;307:331-341. doi: 10.1016/j.jconrel.2019.06.025. Epub 2019 Jun 22.
Lipid nanoparticles are used widely as anticancer drug and gene delivery systems. Internalizing into the target cell is a prerequisite for the proper activity of many nanoparticulate drugs. We show here, that the lipid composition of a nanoparticle affects its ability to internalize into triple-negative breast cancer cells. The lipid headgroup had the greatest effect on enhancing cellular uptake compared to other segments of the molecule. Having a receptor-targeted headgroup induced the greatest increase in cellular uptake, followed by cationic amine headgroups, both being superior to neutral (zwitterion) phosphatidylcholine or to negatively-charged headgroups. The lipid tails also affected the magnitude of cellular uptake. Longer acyl chains facilitated greater liposomal cellular uptake compared to shorter tails, 18:0 > 16:0 > 14:0. When having the same lipid tail length, unsaturated lipids were superior to saturated ones, 18:1 > 18:0. Interestingly, liposomes composed of phospholipids having 14:0 or 12:0-carbon-long-tails, such as DMPC and DLPC, decreased cell viability in a concertation dependent manner, due to a destabilizing effect these lipids had on the cancer cell membrane. Contrarily, liposomes composed of phospholipids having longer carbon tails (16:0 and 18:0), such as DPPC and HSPC, enhanced cancer cell proliferation. This effect is attributed to the integration of the exogenous liposomal lipids into the cancer-cell membrane, supporting the proliferation process. Cholesterol is a common lipid additive in nanoscale formulations, rigidifying the membrane and stabilizing its structure. Liposomes composed of DMPC (14:0) showed increased cellular uptake when enriched with cholesterol, both by endocytosis and by fusion. Contrarily, the effect of cholesterol on HSPC (18:0) liposomal uptake was minimal. Furthermore, the concentration of nanoparticles in solution affected their cellular uptake. The higher the concentration of nanoparticles the greater the absolute number of nanoparticles taken up per cell. However, the efficiency of nanoparticle uptake, i.e. the percent of nanoparticles taken up by cells, decreased as the concentration of nanoparticles increased. This study demonstrates that tuning the lipid composition and concentration of nanoscale drug delivery systems can be leveraged to modulate their cellular uptake.
脂质纳米颗粒被广泛用作抗癌药物和基因传递系统。内吞到靶细胞是许多纳米颗粒药物发挥适当活性的前提。我们在这里表明，纳米颗粒的脂质组成会影响其进入三阴性乳腺癌细胞的能力。与分子的其他部分相比，脂质头部基团对增强细胞摄取的影响最大。具有受体靶向头部基团会引起细胞摄取的最大增加，其次是阳离子胺头部基团，这两者均优于中性（两性离子）磷脂酰胆碱或带负电荷的头部基团。脂质尾部也会影响细胞摄取的程度。与较短的尾部相比，长酰基链会促进更大的脂质体细胞摄取，18:0>16:0>14:0。当具有相同的脂质尾长时，不饱和脂质优于饱和脂质，18:1>18:0。有趣的是，由具有 14:0 或 12:0 个碳原子长链的磷脂组成的脂质体，如 DMPC 和 DLPC，由于这些脂质对癌细胞膜具有破坏作用，会以浓度依赖的方式降低细胞活力。相反，由具有较长碳尾（16:0 和 18:0）的磷脂组成的脂质体，如 DPPC 和 HSPC，则会增强癌细胞的增殖。这种作用归因于外源性脂质体脂质整合到癌细胞膜中，从而支持增殖过程。胆固醇是纳米级配方中常用的脂质添加剂，可使膜变硬并稳定其结构。用胆固醇富集的 DMPC（14:0）组成的脂质体通过内吞作用和融合作用增加了细胞摄取。相反，胆固醇对 HSPC（18:0）脂质体摄取的影响最小。此外，纳米颗粒在溶液中的浓度会影响其细胞摄取。纳米颗粒的浓度越高，每个细胞摄取的纳米颗粒绝对数量就越多。但是，随着纳米颗粒浓度的增加，纳米颗粒摄取的效率（即细胞摄取的纳米颗粒百分比）降低。本研究表明，调整纳米级药物传递系统的脂质组成和浓度可以调节其细胞摄取。
