LP01 & Analogues for Drug Delivery

LP01 & Analogues for Drug Delivery

Published by BroadPharm on January 23, 2024

LP01 is a synthetic ionizable lipid, which is used in the formation of Lipid Nanoparticles (LNPs). These LNPs serve as carriers, effectively encapsulating and transporting RNA, DNA, or small molecules into cells.

Figure 1. Structure of LP01

Most early Lipid Nanoparticles (LNPs) used in clinical applications contained non-degradable ionizable lipids, leading to bioaccumulation in the liver and potential safety concerns. In response to this issue, LP01, with an approximate pKa of 6.1, was specifically designed to be biodegradable through labile ester linkages on the lipid head. LP01 demonstrated liver clearance, and particularly a notable difference from DLin-MC3-DMA, a lipid in clinical trials that showed minimal degradation over 24 hours. The administration of LP01-LNPs was safe and well-tolerated in mice and rats, considering cytokine stimulation and body weight loss. The team at Intellia Therapeutics illustrated the capability of an LP01-based lipid nanoparticle (LNP) system in delivering CRISPR/Cas9 components to attain in vivo genome editing at levels deemed clinically significant. Their research demonstrated how LP01-LNPs are transient and well-tolerated (Finn).

BroadPharm's Offerings

To further optimize and empower drug delivery R&D, BroadPharm developed a gamut of LP01 analogues with modifications of the chargeable amine head, carbonate linkage chain, and/or various lipid tails. As demonstrated below...

One head modification is represented by BP Lipid 401 (Structure A), where the piperidine, a key saturated heterocyclic scaffold, and a carbonate ester are linked to LP01's unmodified linoleic acid (18:2) and two octanoic acid (8:0) tails.

Structure A

Another modification of the head is depicted by BP Lipid 405, (Structure B), where azetidine, a highly rigid 4-member ring, and a carbamate are once again linked to LP01's unmodified tails.

Structure B

The third adjustment is illustrated by BP Lipid 388 (Structure C), where 3-hydroxyazetidine, a water-soluble hydroxyl group attached to an azetidine ring, and two oleic acid tails (18:1) are linked through an ester bond.

Structure C

The fourth modification is exemplified by BP Lipid 351 (Structure D), where 1-(2-Hydroxyethyl)piperazine, a water-soluble hydroxyl group attached to a multi-chargeable piperazine that may permit repeated doses of LNP with enhanced potency and safety (Kim M), and two oleic acid tails (18:1) are linked through an ester bond.

Structure D

Lipid supplier and customer synthesis

As a leading drug delivery lipid supplier worldwide, BroadPharm offers a wide array of ionizable lipids, PEG lipids, phospholipids, and helper lipids. BroadPharm also provides fast speed custom synthesis of novel lipid molecules to empower your advanced research.

Journal References

Kim M, Jeong M, Lee G, et al. Novel piperazine-based ionizable lipid nanoparticles allow the repeated dose of mRNA to fibrotic lungs with improved potency and safety. Bioeng Transl Med. 2023; 8(6):e10556. doi:10.1002/btm2.10556

Finn, Jonathan D., et al. "A single administration of CRISPR/Cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing." Cell reports 22.9 (2018): 2227-2235. doi: https://doi.org/10.1016/j.celrep.2018.02.014