SM-102 is a synthetic ionizable amino lipid that has been widely used to combine with other lipids to form lipid nanoparticles [1,2]. Administration of luciferase mRNA in SM-102-containing lipid nanoparticles can induce hepatic luciferase expression in mice[3]. The formulation containing sm-102 has been significantly used to develop lipid nanoparticles for delivery of mRNA based vaccines [4.5], as this efficient transfection method based on compressed lipopolysamine coated plasmids has been developed [6].
SM-102 addition was effective at blocking IK(erg) in a concentration-dependent fashion with a half-maximal concentration (IC50 ) of 108 μM, a value which is similar to the KD value (i.e., 134 μM) required for its accentuation of deactivation time constant of the current. The hysteretic strength of IK(erg) in response to the long-lasting isosceles-triangular ramp pulse was effectively decreased in the presence of SM-102.
SM-102 (100 μM) diminished the current magnitude further. In MA-10 Leydig cells, the IK(erg) was also blocked by the presence of SM-102. The IC50 value for SM-102-induced inhibition of IK(erg) in MA-10 cells was 98 μM [7]. In BV2 microglial cells, the amplitude of the inwardly rectifying K+ current was inhibited by SM-102. The presence of SM-102 concentration-dependently inhibited IK(erg) in endocrine cells (e.g., GH3 or MA-10 cells).
SM-102 has been implicated in the development of myocarditis following covid-19 vaccination [8,9]. However, the need remains unmet whether sm-102 exerts any perturbation on the magnitude of transmembrane ionic currents. Since the sizes of IK (IR) and IK (ERG) are widely expressed in cardiac cells [10], the inhibitory effect of sm-102 in altering IK (IR) and / or IK (ERG) may potentially participate in the functional activity of cardiac function. These polycationic molecules enter the KIR or kerg channel pore from the intracellular side and block the movement of K + ions through the channel at depolarized potentials, thereby ensuring a longer plateau phase of the cardiac action potential [11]. However, to what extent SM-102-mediated perturbations of membrane ionic currents confer their effectiveness against adverse effects of mRNA based vaccines remains to be further delineated.
参考文献:
[1].Sabnis S, Kumarasinghe E S, Salerno T, et al. A novel amino lipid series for mRNA delivery: improved endosomal escape and sustained pharmacology and safety in non-human primates[J]. Molecular Therapy, 2018, 26(6): 1509-1519.
[2].Hassett K J, Benenato K E, Jacquinet E, et al. Optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines[J]. Molecular Therapy-Nucleic Acids, 2019, 15: 1-11.
[3].Tao W, Davide J P, Cai M, et al. Noninvasive Imaging of Lipid Nanoparticle-Mediated Systemic [4].Delivery of Small-Interfering RNA to the Liver[J]. Molecular Therapy, 2010, 18(9): 1657-1666.
[4]Reichmuth A M, Oberli M A, Jaklenec A, et al. mRNA vaccine delivery using lipid nanoparticles[J]. Therapeutic delivery, 2016, 7(5): 319-334.
[5]Tenchov R, Bird R, Curtze A E, et al. Lipid Nanoparticles─ From Liposomes to mRNA Vaccine Delivery, a Landscape of Research Diversity and Advancement[J]. ACS nano, 2021, 15(11): 16982-17015.
[6]Behr J P, Demeneix B, Loeffler J P, et al. Efficient gene transfer into mammalian primary endocrine cells with lipopolyamine-coated DNA[J]. Proceedings of the National Academy of Sciences, 1989, 86(18): 6982-6986.
[7].Cho H Y, Chuang T H, Wu S N. Effective Perturbations on the Amplitude and Hysteresis of Erg-Mediated Potassium Current Caused by 1-Octylnonyl 8-[(2-hydroxyethyl)[6-oxo-6 (undecyloxy) hexyl] amino]-octanoate (SM-102), a Cationic Lipid[J]. Biomedicines, 2021, 9(10): 1367.
[8]Vidula M K, Ambrose M, Glassberg H, et al. Myocarditis and other cardiovascular complications of the mRNA-based COVID-19 vaccines[J]. Cureus, 2021, 13(6).
[9]Williams C B, Choi J, Hosseini F, et al. Acute myocarditis following mRNA-1273 SARS-CoV-2 vaccination[J]. CJC open, 2021, 3(11): 1410-1412.
[10]Martinson A S, Van Rossum D B, Diatta F H, et al. Functional evolution of Erg potassium channel gating reveals an ancient origin for IKr[J]. Proceedings of the National Academy of Sciences, 2014, 111(15): 5712-5717.
[11]Sung R J, Wu S N, Wu J S, et al. Electrophysiological mechanisms of ventricular arrhythmias in relation to Andersen-Tawil syndrome under conditions of reduced I K1: a simulation study[J]. American Journal of Physiology-Heart and Circulatory Physiology, 2006, 291(6): H2597-H2605.
SM-102 是一种合成的可电离氨基脂质，已广泛用于与其他脂质结合形成脂质纳米颗粒[1,2]。在含有 SM-102 的脂质纳米粒中施用荧光素酶 mRNA 可诱导小鼠肝脏荧光素酶表达[3]。含有 sm-102 的制剂已被大量用于开发用于递送基于 mRNA 的疫苗的脂质纳米颗粒[4.5]，因为这种基于压缩脂多胺包被质粒的高效转染方法已被开发出来[6 ].
添加 SM-102 以浓度依赖性方式有效阻断 IK(erg)，半数最大浓度 (IC50 ) 为 108 μM，该值与 KD 相似值（即 134 μM），用于加重电流的失活时间常数。 SM-102的存在有效降低了IK(erg)对长效等腰三角形斜坡脉冲的滞后强度。
SM-102 (100 μM) 进一步降低了电流幅度。在 MA-10 Leydig 细胞中，IK(erg) 也因 SM-102 的存在而被阻断。 SM-102 诱导的 IK(erg) 抑制在 MA-10 细胞中的 IC50 值为 98 μM [7]。在 BV2 小胶质细胞中，内向整流 K+ 电流的幅度被 SM-102 抑制。 SM-102 浓度依赖性地抑制内分泌细胞（例如 GH3 或 MA-10 细胞）中的 IK(erg)。
SM-102 与 covid-19 疫苗接种后心肌炎的发展有关[8,9]。然而，sm-102 是否对跨膜离子电流的大小施加任何扰动的需求仍未得到满足。由于 IK (IR) 和 IK (ERG) 的大小在心肌细胞[10] 中广泛表达，因此 sm-102 在改变 IK (IR) 和/或 IK (ERG) 方面的抑制作用可能潜在地参与心脏功能的功能活动。这些聚阳离子分子从细胞内侧进入 KIR 或 kerg 通道孔，阻断 K + 离子在去极化电位下通过通道，从而确保心脏动作电位的平台期较长[11] .然而，SM-102 介导的膜离子电流扰动在多大程度上赋予它们对抗基于 mRNA 的疫苗的副作用的有效性仍有待进一步阐明。
| Cell experiment [1]: | |
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Cell lines |
GH3 pituitary tumor cells |
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Preparation Method |
The electrophysiological measurements and whole cell current recording tests were performed 5 or 6 days after cells were subcultured (60-80% confluence). GH3 cells were exposed to SM-102 at concentrations of 100 or 300μM. |
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Reaction Conditions |
100μM /300μM 1min |
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Applications |
The peak or sustained component of the inactivating IK (ERG) evoked by a long hyperpolarizing pulses -10 to -90 mV gradually decreased 1 min after GH3 cells were exposed to SM-102 at concentrations of 100 or 300μM. As the rectangular voltage step from -10 to -90 mV with a duration of 1 s was delivered to the examined cell to activate IK(erg), the application of 300 μM SM-102 was noticed to result in a conceivable reduction in the peak or sustained amplitude of IK(erg) to 119 ± 34 or 22 ± 4 pA from control values of 174 ± 43 or 46 ± 7 pA respectively. After a washout of SM-102, the initial IK(erg) was reversed to 169 ± 39 pA. The application of 100 μM SM-102 to cells led to a reduction in IK(erg) amplitude during the upsloping or downsloping limb of the triangular ramp pulse by about 18% or 28%, respectively. The IC50 value required for the SM-102-mediated inhibition of IK(erg) observed in MA-10 cells was estimated to be 98 μM. |
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参考文献: [1]. Cho H Y, Chuang T H, Wu S N. Effective Perturbations on the Amplitude and Hysteresis of Erg-Mediated Potassium Current Caused by 1-Octylnonyl 8-[(2-hydroxyethyl)[6-oxo-6 (undecyloxy) hexyl] amino]-octanoate (SM-102), a Cationic Lipid[J]. Biomedicines, 2021, 9(10): 1367. |
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