Advancements in Lipids for Drug Delivery

Advancements in Lipids for Drug Delivery

Published by BroadPharm on February 23, 2024

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...

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 (Lam). To fine-tune its properties, BroadPharm synthesized a range of analogs, incorporating alterations between the chargeable tertiary amine head, bridge chain, and hydrophobic fatty acid tails linked through an ester or amide bond (see Figure 1).

Figure 1: Alteration Sites of SM-102

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 (Kazemian). 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 (see Figure 2).

Figure 2: Alteration Sites of LP01

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 (Tang). A range of analogs were created 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 (see Figure 3).

Figure 3: Alteration Sites of TCL053

Multi Chargeable Lipids

Multichargable lipids like C3-K2-E14 (see Figure 4) incorporate three tertiary amines for improved RNA binding and include hydroxyl and amide motifs to enhance RNA binding and LNP stability (Manning). BP Lipid 372 (see Figure 5), 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 (Hashiba).

Figure 4: Structure of C3-K2-E14

Figure 5: Structure of BP Lipid 372

Other Ionizable Lipids

Lipids like CL15H6 (see Figure 6), 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 (Sato). 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.

Figure 6: Structure of CL15H6

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

Lam, K., Leung, A., Martin, A., Wood, M., Schreiner, P., Palmer, L., ... & Heyes, J. (2023). Unsaturated, Trialkyl Ionizable Lipids are Versatile Lipid-Nanoparticle Components for Therapeutic and Vaccine Applications. Advanced Materials, 35(15), 2209624.

Kazemian, P., Yu, S. Y., Thomson, S. B., Birkenshaw, A., Leavitt, B. R., & Ross, C. J. (2022). Lipid-nanoparticle-based delivery of CRISPR/Cas9 genome-editing components. Molecular Pharmaceutics, 19(6), 1669-1686.

Tang, X., Zhang, Y., & Han, X. (2023). Ionizable Lipid Nanoparticles for mRNA Delivery. Advanced NanoBiomed Research, 3(8), 2300006.

Manning, A. M., Tilstra, G., Khan, A. B., Couture-Senécal, J., Lau, Y. M. A., Pang, J., ... & Khan, O. F. (2023). Ionizable Lipid with Supramolecular Chemistry Features for RNA Delivery In Vivo. Small, 2302917.

Hashiba, K., Sato, Y., Taguchi, M., Sakamoto, S., Otsu, A., Maeda, Y., ... & Harashima, H. (2023). Branching Ionizable Lipids Can Enhance the Stability, Fusogenicity, and Functional Delivery of mRNA. Small Science, 3(1), 2200071.

Sato, Y., Okabe, N., Note, Y., Hashiba, K., Maeki, M., Tokeshi, M., & Harashima, H. (2020). Hydrophobic scaffolds of pH-sensitive cationic lipids contribute to miscibility with phospholipids and improve the efficiency of delivering short interfering RNA by small-sized lipid nanoparticles. Acta biomaterialia, 102, 341-350.