Dear Researchers,

The success of COVID-19 vaccines has ignited a significant surge in nanoparticle drug delivery R&D. Among the four key components of lipid nanoparticles (LNPs) – ionizable lipids, phospholipids, cholesterol, and PEG lipids - ionizable lipids (e.g. ALC-0315, SM-102, D-Lin-MC3-DMA) are the most crucial and undergo protonation in acidic conditions, making them essential for efficient drug transport. 

BroadPharm has synthesized a variety of ionizable lipid analogs to optimize and explore the full potential of lipids in nanoparticle drug delivery. Our wide range of prominent lipids and novel analogs enable and expedite therapeutic discovery.

 Learn more about our Ionizable lipid classes: 

Analogs of SM-102: SM-102 (pKa 6.68) is known for its use in the FDA-approved Moderna COVID-19 vaccine mRNA-1273. It exhibits an excellent pharmacokinetic profile due to its fast blood clearance rate. To further fine-tune SM-102-LNP properties, BroadPharm synthesized a range of analogs, incorporating alterations between the chargeable tertiary amine head, bridge chain, and various hydrophobic fatty acid tails linked through an ester or amide bond. 

LP01 & Analogs: LP01 (pKa 6.1) effectively delivers CRISPR/Cas9 components and is well-tolerated in animal studies. It shows advantages in biodegradability and liver clearance. A series of analogs have been developed with alterations to the chargeable amine head (e.g. replacement by an azetidine or other ring), carbonate linkage (replacement by an ester or carbamate bond), and different lipid tails.

TCL053 & Analogs: TCL053 (pKa 6.8), another valuable ionizable lipid, has been used in LNPs to deliver CRISPR-Cas9 mRNA and sgRNA to multiple muscle tissues with low immunogenicity and an enhanced safety profile. It shows a promising outlook to treat diseases like Duchenne muscular dystrophy, which require multiple doses. A range of analogs have been synthesized with modifications to the head (e.g. replacement by a multi-chargeable piperazine or other ring) and hydrophobic tails (e.g. from 3 to 2 tails) to optimize TCL053-LNP delivery.  

Multi Chargeable Lipids: Multichargable lipids like C3-K2-E14 incorporate three tertiary amines for improved RNA binding and include hydroxyl and amide motifs to enhance RNA binding and LNP stability. BP Lipid 372, characterized by a PEG4 linkage and four cis-double bonds, facilitates endosomal fusion, cytosol delivery, and hydrophilicity. Highly symmetric lipids such as these and others contribute to controlled particle size, maximizing the ionization ability of head groups through branched chains, increasing lipid nanoparticle viscosity, and promoting mRNA expression in the liver and spleen.

Advanced Lipids: Lipids like CL15H6, a type of ionizable cationic lipid (CL), possess longer scaffolds (C24 + O1). These extended scaffolds make it immiscible with typical lipids found in the cell membrane, phosphatidylcholines (PCs), and sphingolipids (SMs). PCs and SMs inhibit the L-to-HII phase transition only when fusogenic CLs are miscible with them during the phase transition. As a result, CL15H6 is resistant to the inhibitory effects of these lipids during membrane fusion, which contributes significantly to efficient endosomal escape. As shown in BroadPharm’s website, analogous lipids such as BP Lipid 411 and BP Lipid 413 feature alterations to the head and tail groups to fine-tune LNP properties and delivery.

Exploring BroadPharm’s vast array of ionizable lipid solutions — from analogs of SM-102 to multi chargeable lipids and beyond  — opens doors to a future where RNA therapeutics flourish. Let us unlock the potential together.

 

Ready to elevate your research? Visit our website to explore our full range of ionizable lipids.