Functional Lipids

1. Lipids for Active Targeting

History of liposome research

First Generation
First Generation Classic liposomes consisting of typical phospholipids and cholesterol
Second Generation
Second Generation Liposomes with long circulation by modifying the liposome surface with PEG. Accumulation in solid cancer can be enhanced by the EPR effect.
Third Generation
Third Generation Liposomes surface can be modified with PEG and targeting molecules such as antibodies and peptides to increase the retention in the blood and further improve the migration to the target site.

PEG-Binded Phospholipids

Used for long circulating liposomes
such as DOXIL®.		 MPEG-DSPE
Peptide-Binded PEG lipid
(Joint research with Professor Oku
at University of Shizuoka)		 Peptide-Binded PEG lipid

Biodistribution of Peptide-PEG-modified Liposomes

Biodistribution of Peptide-PEG-modified Liposomes

APRPG-PEG-modified liposomes accumulated significantly in the tumor tissue 24 hours after administration than only PEG-modified liposomes.

Distribution in the Tumor Tissue of Peptide-PEG-modified liposomes

Red Images: Liposomes, Green Images: Vascular endothelial cells

  • Non-modified liposomeNon-modified liposome
  • PEG-modified liposomePEG-modified liposome
  • APRPG-PEG-modified liposomeAPRPG-PEG-modified liposome

PEG-modified liposomes were observed to leak out of tumor neovasculature due to the EPR effect and remain at the marginal region of the blood vessels.
On the other hand, APRPG-PEG-modified liposomes were observed to adhere to and take up vascular endothelial cells in addition to leakage outside the blood vessels, indicating that the liposomes could be targeted by the effect of peptide modification.

Solid tumor regression effect by peptide-PEG-modified liposome encapsulating doxorubicin

Solid tumor regression effect by peptide-PEG-modified liposome encapsulating doxorubicin

In the APRPG-PEG-modified liposomal doxorubicin, the tumor size was significantly reduced compared to other groups.

Maeda N. et al., Bioorg. Med. Chem. Lett., 14, 1015 (2004)
Maeda N. et al., J. Control. Release, 100, 41 (2004)
Maeda N. et al., Biol. Phanm. Bull., 29(9), 1936 (2006)

2. Charge-Reversible Lipid

DOP-DEDA

DOP-DEDA

Structure of Lipid Nano Particle [LNP]

Structure of Lipid Nano Particle [LNP]
Particle Size Encapsulation efficacy of siRNA ζ-Potential
㏗ ㎷
95 ± 5 ㎚ 96.4% 7.4 -24.6
5.6 +8.2
4.7 +30.0
Structure of Lipid Nano Particle [LNP]

Target gene silencing using LNP

Structure of Lipid Nano Particle [LNP]

Knockdown of target protein using LNP

3. DHSM

DHSM(Dihydrosphingomyelin)

DHSM

We have developed commercial production technology for DHSM (dihydrosphingomyelin) under GMP condition.
Since DHSM is a completely synthetic product, unlike natural products, the length of its side chain is constant. It has advantages such as easy quality control because it is hard to oxidize or hydrolyze.
And this compound has long-circulation than those of generally used phospholipids.

(Reference: WO2018/181963, Biochimica et Biophysica Acta 1768 (2007) 1121)

Practical Example

DHSM was applied by Fujifilm to their FF-10850 liposome formulation, and it is currently undergoing Phase 1 trials in the United States.

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