SM-102
(Synonyms: Lipid H) 目录号 : GC48385
An ionizable cationic amino lipid
Cas No.:2089251-47-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| 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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References: [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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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.
References:
[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。
| Cas No. | 2089251-47-6 | SDF | |
| 别名 | Lipid H | ||
| Canonical SMILES | OCCN(CCCCCCCC(OC(CCCCCCCC)CCCCCCCC)=O)CCCCCC(OCCCCCCCCCCC)=O | ||
| 分子式 | C44H87NO5 | 分子量 | 710.2 |
| 溶解度 | Ethanol : ≥ 100 mg/mL (140.81 mM) DMSO ;100 mg/mL (140.81 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.4081 mL | 7.0403 mL | 14.0805 mL |
| 5 mM | 0.2816 mL | 1.4081 mL | 2.8161 mL |
| 10 mM | 0.1408 mL | 0.704 mL | 1.4081 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Optimization of Lipid Nanoparticles for saRNA Expression and Cellular Activation Using a Design-of-Experiment Approach
Mol Pharm 2022 Jun 6;19(6):1892-1905.PMID:PMC9176215DOI:10.1021/acs.molpharmaceut.2c00032.
Lipid nanoparticles (LNPs) are the leading technology for RNA delivery, given the success of the Pfizer/BioNTech and Moderna COVID-19 mRNA (mRNA) vaccines, and small interfering RNA (siRNA) therapies (patisiran). However, optimization of LNP process parameters and compositions for larger RNA payloads such as self-amplifying RNA (saRNA), which can have complex secondary structures, have not been carried out. Furthermore, the interactions between process parameters, critical quality attributes (CQAs), and function, such as protein expression and cellular activation, are not well understood. Here, we used two iterations of design of experiments (DoE) (definitive screening design and Box-Behnken design) to optimize saRNA formulations using the leading, FDA-approved ionizable lipids (MC3, ALC-0315, and SM-102). We observed that PEG is required to preserve the CQAs and that saRNA is more challenging to encapsulate and preserve than mRNA. We identified three formulations to minimize cellular activation, maximize cellular activation, or meet a CQA profile while maximizing protein expression. The significant parameters and design of the response surface modeling and multiple response optimization may be useful for designing formulations for a range of applications, such as vaccines or protein replacement therapies, for larger RNA cargoes.
Comparison of DLin-MC3-DMA and ALC-0315 for siRNA Delivery to Hepatocytes and Hepatic Stellate Cells
Mol Pharm 2022 Jul 4;19(7):2175-2182.PMID:PMC9621687DOI:10.1021/acs.molpharmaceut.2c00033.
Ionizable cationic lipids are essential for efficient in vivo delivery of RNA by lipid nanoparticles (LNPs). DLin-MC3-DMA (MC3), ALC-0315, and SM-102 are the only ionizable cationic lipids currently clinically approved for RNA therapies. ALC-0315 and SM-102 are structurally similar lipids used in SARS-CoV-2 mRNA vaccines, while MC3 is used in siRNA therapy to knock down transthyretin in hepatocytes. Hepatocytes and hepatic stellate cells (HSCs) are particularly attractive targets for RNA therapy because they synthesize many plasma proteins, including those that influence blood coagulation. While LNPs preferentially accumulate in the liver, evaluating the ability of different ionizable cationic lipids to deliver RNA cargo into distinct cell populations is important for designing RNA-LNP therapies with minimal hepatotoxicity. Here, we directly compared LNPs containing either ALC-0315 or MC3 to knock-down coagulation factor VII (FVII) in hepatocytes and ADAMTS13 in HSCs. At a dose of 1 mg/kg siRNA in mice, LNPs with ALC-0315 achieved a 2- and 10-fold greater knockdown of FVII and ADAMTS13, respectively, compared to LNPs with MC3. At a high dose (5 mg/kg), ALC-0315 LNPs increased markers of liver toxicity (ALT and bile acids), while the same dose of MC3 LNPs did not. These results demonstrate that ALC-0315 LNPs achieves potent siRNA-mediated knockdown of target proteins in hepatocytes and HSCs, in mice, though markers of liver toxicity can be observed after a high dose. This study provides an initial comparison that may inform the development of ionizable cationic LNP therapeutics with maximal efficacy and limited toxicity.
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
Biomedicines 2021 Oct 1;9(10):1367.PMID:34680484DOI:10.3390/biomedicines9101367.
SM-102 (1-octylnonyl 8-[(2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino]-octanoate) is an amino cationic lipid that has been tailored for the formation of lipid nanoparticles and it is one of the essential ingredients present in the ModernaTM COVID-19 vaccine. However, to what extent it may modify varying types of plasmalemmal ionic currents remains largely uncertain. In this study, we investigate the effects of SM-102 on ionic currents either in two types of endocrine cells (e.g., rat pituitary tumor (GH3) cells and mouse Leydig tumor (MA-10) cells) or in microglial (BV2) cells. Hyperpolarization-activated K+ currents in these cells bathed in high-K+, Ca2+-free extracellular solution were examined to assess the effects of SM-102 on the amplitude and hysteresis of the erg-mediated K+ current (IK(erg)). The 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. Cell exposure to TurboFectinTM 8.0 (0.1%, v/v), a transfection reagent, was able to inhibit hyperpolarization-activated IK(erg) effectively with an increase in the deactivation time course of the current. Additionally, in GH3 cells dialyzed with spermine (30 μM), the IK(erg) amplitude progressively decreased; moreover, a further bath application of SM-102 (100 μM) or TurboFectin (0.1%) diminished the current magnitude further. In MA-10 Leydig cells, the IK(erg) was also blocked by the presence of SM-102 or TurboFectin. The IC50 value for SM-102-induced inhibition of IK(erg) in MA-10 cells was 98 μM. In BV2 microglial cells, the amplitude of the inwardly rectifying K+ current was inhibited by SM-102. Taken together, the presence of SM-102 concentration-dependently inhibited IK(erg) in endocrine cells (e.g., GH3 or MA-10 cells), and such action may contribute to their functional activities, assuming that similar in vivo findings exist.
Effective Perturbations by Small-Molecule Modulators on Voltage-Dependent Hysteresis of Transmembrane Ionic Currents
Int J Mol Sci 2022 Aug 21;23(16):9453.PMID:36012718DOI:10.3390/ijms23169453.
The non-linear voltage-dependent hysteresis (Hys(V)) of voltage-gated ionic currents can be robustly activated by the isosceles-triangular ramp voltage (Vramp) through digital-to-analog conversion. Perturbations on this Hys(V) behavior play a role in regulating membrane excitability in different excitable cells. A variety of small molecules may influence the strength of Hys(V) in different types of ionic currents elicited by long-lasting triangular Vramp. Pirfenidone, an anti-fibrotic drug, decreased the magnitude of Ih's Hys(V) activated by triangular Vramp, while dexmedetomidine, an agonist of α2-adrenoceptors, effectively suppressed Ih as well as diminished the Hys(V) strength of Ih. Oxaliplatin, a platinum-based anti-neoplastic drug, was noted to enhance the Ih's Hys(V) strength, which is thought to be linked to the occurrence of neuropathic pain, while honokiol, a hydroxylated biphenyl compound, decreased Ih's Hys(V). Cell exposure to lutein, a xanthophyll carotenoid, resulted in a reduction of Ih's Hys(V) magnitude. Moreover, with cell exposure to UCL-2077, SM-102, isoplumbagin, or plumbagin, the Hys(V) strength of erg-mediated K+ current activated by triangular Vramp was effectively diminished, whereas the presence of either remdesivir or QO-58 respectively decreased or increased Hys(V) magnitude of M-type K+ current. Zingerone, a methoxyphenol, was found to attenuate Hys(V) (with low- and high-threshold loops) of L-type Ca2+ current induced by long-lasting triangular Vramp. The Hys(V) properties of persistent Na+ current (INa(P)) evoked by triangular Vramp were characterized by a figure-of-eight (i.e., ∞) configuration with two distinct loops (i.e., low- and high-threshold loops). The presence of either tefluthrin, a pyrethroid insecticide, or t-butyl hydroperoxide, an oxidant, enhanced the Hys(V) strength of INa(P). However, further addition of dapagliflozin can reverse their augmenting effects in the Hys(V) magnitude of the current. Furthermore, the addition of esaxerenone, mirogabalin, or dapagliflozin was effective in inhibiting the strength of INa(P). Taken together, the observed perturbations by these small-molecule modulators on Hys(V) strength in different types of ionic currents evoked during triangular Vramp are expected to influence the functional activities (e.g., electrical behaviors) of different excitable cells in vitro or in vivo.
Prediction of lipid nanoparticles for mRNA vaccines by the machine learning algorithm
Acta Pharm Sin B 2022 Jun;12(6):2950-2962.PMID:35755271DOI:10.1016/j.apsb.2021.11.021.
Lipid nanoparticle (LNP) is commonly used to deliver mRNA vaccines. Currently, LNP optimization primarily relies on screening ionizable lipids by traditional experiments which consumes intensive cost and time. Current study attempts to apply computational methods to accelerate the LNP development for mRNA vaccines. Firstly, 325 data samples of mRNA vaccine LNP formulations with IgG titer were collected. The machine learning algorithm, lightGBM, was used to build a prediction model with good performance (R 2 > 0.87). More importantly, the critical substructures of ionizable lipids in LNPs were identified by the algorithm, which well agreed with published results. The animal experimental results showed that LNP using DLin-MC3-DMA (MC3) as ionizable lipid with an N/P ratio at 6:1 induced higher efficiency in mice than LNP with SM-102, which was consistent with the model prediction. Molecular dynamic modeling further investigated the molecular mechanism of LNPs used in the experiment. The result showed that the lipid molecules aggregated to form LNPs, and mRNA molecules twined around the LNPs. In summary, the machine learning predictive model for LNP-based mRNA vaccines was first developed, validated by experiments, and further integrated with molecular modeling. The prediction model can be used for virtual screening of LNP formulations in the future.