5A2-SC8
目录号 : GC64809
5A2-SC8 是一种可降解的类脂化合物（酯基树突状分子），用于小RNA 递送。
Cas No.:1857341-90-2
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
5A2-SC8 is a degradable lipid-like compound (ester-based dendrimer) for small RNAs delivery.
[1]. Zhou K, Nguyen LH, Miller JB, et al. Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model. Proc Natl Acad Sci U S A. 2016;113(3):520-525.
| Cas No. | 1857341-90-2 | SDF | Download SDF |
| 分子式 | C93H173N5O20S5 | 分子量 | 1841.72 |
| 溶解度 | 储存条件 | Store at -20°C,protect from light | |
| 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 | 0.543 mL | 2.7149 mL | 5.4297 mL |
| 5 mM | 0.1086 mL | 0.543 mL | 1.0859 mL |
| 10 mM | 0.0543 mL | 0.2715 mL | 0.543 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。
Dendrimer-Based Lipid Nanoparticles Deliver Therapeutic FAH mRNA to Normalize Liver Function and Extend Survival in a Mouse Model of Hepatorenal Tyrosinemia Type I
Adv Mater 2018 Dec;30(52):e1805308.PMID:30368954DOI:10.1002/adma.201805308.
mRNA-mediated protein replacement represents a promising concept for the treatment of liver disorders. Children born with fumarylacetoacetate hydrolase (FAH) mutations suffer from Hepatorenal Tyrosinemia Type 1 (HT-1) resulting in renal dysfunction, liver failure, neurological impairments, and cancer. Protein replacement therapy using FAH mRNA offers tremendous potential to cure HT-1, but is currently hindered by the development of effective mRNA carriers that can function in diseased livers. Structure-guided, rational optimization of 5A2-SC8 mRNA-loaded dendrimer lipid nanoparticles (mDLNPs) increases delivery potency of FAH mRNA, resulting in functional FAH protein and sustained normalization of body weight and liver function in FAH-/- knockout mice. Optimization using luciferase mRNA produces DLNP carriers that are efficacious at mRNA doses as low as 0.05 mg kg-1 in vivo. mDLNPs transfect > 44% of all hepatocytes in the liver, yield high FAH protein levels (0.5 mg kg-1 mRNA), and are well tolerated in a knockout mouse model with compromised liver function. Genetically engineered FAH-/- mice treated with FAH mRNA mDLNPs have statistically equivalent levels of TBIL, ALT, and AST compared to wild type C57BL/6 mice and maintain normal weight throughout the month-long course of treatment. This study provides a framework for the rational optimization of LNPs to improve delivery of mRNA broadly and introduces a specific and viable DLNP carrier with translational potential to treat genetic diseases of the liver.
Hydrophobic Domain Structure of Linear-Dendritic Poly(ethylene glycol) Lipids Affects RNA Delivery of Lipid Nanoparticles
Mol Pharm 2020 May 4;17(5):1575-1585.PMID:32267707DOI:10.1021/acs.molpharmaceut.9b01288.
In this work, a series of linear-dendritic poly(ethylene glycol) (PEG) lipids (PEG-GnCm) were synthesized through a strategy using sequential aza- and sulfa-Michael addition reactions. The effect of modulating the hydrophobic domain of linear-dendritic PEG lipids was systematically investigated for in vitro and in vivo small RNA delivery as the surface-stabilizing component of 5A2-SC8 dendrimer lipid-based nanoparticles (DLNPs). The lipid alkyl lengths (C8, C12, and C16) and dendrimer generations (G1, G2, and G3) were altered to create PEG-GnCm with different physical properties and anchoring potential. The tail chemical structure of PEG-GnCm did not affect the formulation of 5A2-SC8 DLNPs, including the nanoparticle size, RNA encapsulation, and stability. However, the tail chemical structure did dramatically affect the RNA delivery efficacy of the formed 5A2-SC8 DLNPs with different PEG-GnCm. First-generation PEG lipids (PEG-G1C8, PEG-G1C12, and PEG-G1C16) and a second-generation PEG lipid (PEG-G2C8) formed 5A2-SC8 DLNPs that could deliver siRNAs effectively in vitro and in vivo. 5A2-SC8 DLNPs formulated with second-generation PEG lipids (PEG-G2C12 and PEG-G2C16) and all three third-generation PEG lipids (PEG-G3C8, PEG-G3C12, and PEG-G3C16) lost the ability to deliver siRNA effectively in vitro and in vivo. Overall, we determined that the hydrophobic domain chemical structure of linear-dendritic poly(ethylene glycol) lipids affected the RNA delivery of DLNPs by impacting the escape of 5A2-SC8 DLNPs from endosomes at early cell incubation times, thereby indicating how PEG lipid anchoring and chemical structure can modulate in vitro and in vivo siRNA delivery efficacies.
Lipid Nanoparticle (LNP) Chemistry Can Endow Unique In Vivo RNA Delivery Fates within the Liver That Alter Therapeutic Outcomes in a Cancer Model
Mol Pharm 2022 Nov 7;19(11):3973-3986.PMID:PMC9888001DOI:10.1021/acs.molpharmaceut.2c00442.
Within the field of lipid nanoparticles (LNPs) for RNA delivery, the focus has been mainly placed on organ level delivery, which can mask cellular level effects consequential to therapeutic applications. Here, we studied a pair of LNPs with similar physical properties and discovered how the chemistry of the ionizable amino lipid can control the endogenous LNP identity, affecting cellular uptake in the liver and altering therapeutic outcomes in a model of liver cancer. Although most LNPs accumulate in the liver after intravenous administration (suggesting that liver delivery is straightforward), we observed an unexpected behavior when comparing two similar LNP formulations (5A2-SC8 and 3A5-SC14 LNPs) that resulted in distinct RNA delivery within the organ. Despite both LNPs possessing similar physical properties, ability to silence gene expression in vitro, strong accumulation within the liver, and a shared pKa of 6.5, only 5A2-SC8 LNPs were able to functionally deliver RNA to hepatocytes. Factor VII (FVII) activity was reduced by 87%, with 5A2-SC8 LNPs carrying FVII siRNA (siFVII), while 3A5-SC14 LNPs carrying siFVII produced baseline FVII activity levels comparable to the nontreatment control at a dosage of 0.5 mg/kg. Protein corona analysis indicated that 5A2-SC8 LNPs bind apolipoprotein E (ApoE), which can drive LDL-R receptor-mediated endocytosis in hepatocytes. In contrast, the surface of 3A5-SC14 LNPs was enriched in albumin but depleted in ApoE, which likely led to Kupffer cell delivery and detargeting of hepatocytes. In an aggressive MYC-driven liver cancer model relevant to hepatocytes, 5A2-SC8 LNPs carrying let-7g miRNA were able to significantly extend survival up to 121 days. Since disease targets exist in an organ- and cell-specific manner, the clinical development of RNA LNP therapeutics will require an improved understanding of LNP cellular tropism within organs. The results from our work illustrate the importance of understanding the cellular localization of RNA delivery and incorporating further checkpoints when choosing nanoparticles beyond biochemical and physical characterization, as small changes in the chemical composition of LNPs can have an impact on both the biofate of LNPs and therapeutic outcomes.
Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model
Proc Natl Acad Sci U S A 2016 Jan 19;113(3):520-5.PMID:26729861DOI:10.1073/pnas.1520756113.
RNA-based cancer therapies are hindered by the lack of delivery vehicles that avoid cancer-induced organ dysfunction, which exacerbates carrier toxicity. We address this issue by reporting modular degradable dendrimers that achieve the required combination of high potency to tumors and low hepatotoxicity to provide a pronounced survival benefit in an aggressive genetic cancer model. More than 1,500 dendrimers were synthesized using sequential, orthogonal reactions where ester degradability was systematically integrated with chemically diversified cores, peripheries, and generations. A lead dendrimer, 5A2-SC8, provided a broad therapeutic window: identified as potent [EC50 < 0.02 mg/kg siRNA against FVII (siFVII)] in dose-response experiments, and well tolerated in separate toxicity studies in chronically ill mice bearing MYC-driven tumors (>75 mg/kg dendrimer repeated dosing). Delivery of let-7 g microRNA (miRNA) mimic inhibited tumor growth and dramatically extended survival. Efficacy stemmed from a combination of a small RNA with the dendrimer's own negligible toxicity, therefore illuminating an underappreciated complication in treating cancer with RNA-based drugs.