Journal
MOLECULAR PHARMACEUTICS
Volume 17, Issue 4, Pages 1397-1404Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.0c00087
Keywords
lipid nanoparticle; ovarian cancer; intraperitoneal injection; siRNA; EpCAM; active targeting
Funding
- Ministry of Health, Labour and Welfare
- Ministry of Education, Culture, Sports, Science, and Technology
- Japan Society for the Promotion of Science KAKENHI [18K18351]
- Ichiro Kanehara Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Grants-in-Aid for Scientific Research [18K18351] Funding Source: KAKEN
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Peptide modification is a popular strategy for developing an active targeting lipid nanoparticle (LNP). In modifying the surface of an LNP with a peptide, the sequence and structure of the peptide strongly affects the formation of the LNP. Specifically, a peptide with a high hydrophobicity can induce coarsening and aggregation of the LNP. In an attempt to prevent this from occurring, we incorporated monoacyl and diacyl group-conjugated poly(ethylene glycol) (PEG) into a LNP. We previously developed an original LNP, a multifunctional envelope type nanodevice (MEND) modified with an Epi-1 peptide, a ligand with a high affinity for the epithelial cell adhesion molecule (EpCAM). Using this peptide-modified MEND, the efficiency of delivery of a small interfering RNA (siRNA) encapsulated in the MEND was significantly improved. Although increasing the ratio of modification enhanced cellular uptake, the increase also induced aggregation of the LNP, particularly in the case of a large scale preparation. Our results indicate that a monoacyl PEG-lipid can prevent aggregation, even when the LNP is modified with higher molar ratios of peptide, but that this also results in a decrease in delivery efficiency. Moreover, the Epi-1-modified MEND exhibited a strong silencing effect in an ovarian cancer peritoneal dissemination model. Our results suggest that the simple incorporation of a monoacyl derivative into the PEG-lipid resulted in the formation of a peptide-modified LNP with improved characteristics.
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