1 research outputs found
Efficient siRNA Delivery by Lipid Nanoparticles Modified with a Nonstandard Macrocyclic Peptide for EpCAM-Targeting
The
development of a specific, effective method for the delivery
of therapeutics including small molecules and nucleic acids to tumor
tissue remains to be solved. Numerous types of lipid nanoparticles
(LNPs) have been developed in attempts to achieve this goal. However,
LNPs are probably not taken up by target cells because cancer-targeting
LNPs are typically modified with polyÂ(ethylene glycol) (PEG), which
inhibits the cellular uptake of LNPs, to passively accumulate in tumor
tissue via the enhanced permeability and retention (EPR) effect. It
would clearly be important to develop a LNP with both a prolonged
circulation and cancer-specific efficient uptake for use in an innovative
nanodrug delivery system. Herein, we assessed the effect of nonstandard
macrocyclic peptides against the epithelial cell adhesion molecule
(EpCAM) Epi-1, which was discovered by a random nonstandard peptides
integrated discovery (RaPID) system, on the cellular uptake and therapeutics
delivery of LNPs. A liposomal siRNA delivery system (MEND) was modified
with an Epi-1 lipid-derivative (EpCAM-targeting MEND; ET-MEND). The
resulting ET-MEND showed a more than 27-fold increase in cellular
uptake in EpCAM-positive cell lines. In the case of negative cells,
cellular uptake and the efficiency of the ET-MEND for delivering therapeutics
were comparable with those of nonmodified MEND. In addition, when
systemically injected, the ET-MEND successfully inhibited gene expression
in the tumor tissue at a dose of 0.5 mg siRNA/kg without any obvious
toxicity. These results suggest that a combination of a specific peptide
ligand can be used to identify a RaPID system and that the use of
such a MEND for liposomal drug delivery has the potential for use
in developing a system for the efficacious delivery of pharmaceuticals
to various cancer cells