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Application of DMG-PEG2000 as a key nucleic acid delivery excipient in RNA drug liposomes

Time:2021-11-22

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In this article, we will talk about the application of cationic liposome DMG-PEG2000, a key excipient for nucleic acid delivery, in RNA drug liposomes.

The role of DMG-PEG2000 in nucleic acid delivery is to prevent aggregation between particles, and to realize long circulation and passive targeting by the "stealth" effect of PEG2000. So why not use DSPE-PEG2000 but to bother to develop a new accessory? According to the original research company Alnylam, the type and quantity of PEGylated lipids used in the prescription not only determine the particle size of liposomes, but also strongly affect the gene silencing ability. Obviously, DSPE has no advantage over DMG-PEG2000 in this point.

Dmg-peg2000 can reduce the interaction between liposomes and cells and the ability of ApoE adsorption. At the same time, the use of polyethylene glycol lipids containing short acyl chain (C14 M) can achieve in vivo escape and rapid dissociation, in vivo half-life <30min, to obtain the best effect of gene silencing in liver cells.

Nucleic acid delivery of key excipients Yang DMG-PEG2000 English full name 1, 2-dimyristoyl-RAC - GLYCERo-3-methoxypolyethylene glycol-2000, Chinese name can be translated as two nutmeg glycerol - polyethylene glycol 2000.

Its molecular formula is C122H242O50, its molecular weight is 2509.2 (average), and its structure is as follows:

From the structural formula, it can be seen that the material is peg-modified a short chain lipid, C14 is much shorter than the C18 chain of the common DSPE-MPEG2000, so the direct result is that the lipid "anchor" inserted into the lipid membrane is "shallow", easy to fall off in the process of systemic circulation. The advantage of this design is that it solves the PEG-Dilemma.

Peg-dilemma has three main points:
1. The steric hindrance of PEG chain shields the interaction between liposomes and cell membrane, and the uptake of liposomes by YI target cells;
2. Shielding the interaction between liposome and endosomal membrane prevents "endosomal escape", resulting in RNA degradation and failure to enter cytoplasm smoothly;
3. Multiple injections of PEGylated liposomes induced immune response, resulting in accelerated blood chu (ABC).

The general solution is to reduce the density of PEG on the liposome surface; Peg-lipid interlinker, such as ester bond, hydrazone bond and peptide bond, can be broken. The use of short-chain lipids, such as C14 lipid-anchored, can dissociate PEG from the particle surface more easily than C18.

In addition, the short chain (mymyritic acid, C14) of DMG-PEG2000 can be degraded faster than the long chain (stearic acid, C18) with a short half-life. Dmg-peg2000 can reduce the interaction between liposomes and cells and the ability of ApoE adsorption, and achieve good gene silencing effect.

"Lysosomal/endosomal escape" is the key and difficulty of RNA drug delivery, and its efficacy is directly related to it. Polyethylene glycol lipids with short alkyl chains can be used to achieve in vivo escape and dissociate rapidly, thus countering the failure of "connotative escape" caused by pegging.

This is why DSPE-MPEG2000 is commonly used in chemical liposomes and nucleic acid liposomes using DMG-PEG2000 have higher gene silencing/expression levels and better efficacy.

Based on this consideration, many new peG-based lipids have been developed, such as DMA-PEG2000, PEG2000-CeramIDE-C14, etc., which can be selected according to needs in scientific research.

| Chinese name: DMG - PEG2000
| trade name: DMG - PEG2000
| chemical name: 1, 2-2 nutmeg acyl - rac - glycerol - 3 - methoxy polyethylene glycol (peg) 2000
| manufacturers: YiWeiTa (Shanghai) pharmaceutical technology co., LTD
| the CAS no. : 160743-62-4
| molecular formula: C32H62O5 (C2H4O) n, n material 45
| purpose: cationic liposomes
| properties: white powder
| solubility: soluble in methanol, chloroform, partly soluble in water.
| molecular weight: 2509.2
| preservation conditions: - 20 ℃
| note: avoid contact with strong acid, strong alkali, strong oxidizing substances
| article number: 002005
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