PLGA Nanoparticle−Peptide Conjugate Effectively Targets Intercellular Cell-Adhesion Molecule-1

Abstract

Targeted delivery of therapeutics possesses the potential to localize therapeutic agents to a specific tissue as a mechanism to enhance treatment efficacy and abrogate side effects. Antibodies have been used clinically as therapeutic agents and are currently being explored for targeting drug-loaded nanoparticles. Peptides such as RGD peptides are also being developed as an inexpensive and stable alternative to antibodies. In this study, cyclo(1,12)PenITDGEATDSGC (cLABL) peptide was used to target nanoparticles to human umbilical cord vascular endothelial cells (HUVEC) monolayers that have upregulated intercellular cell-adhesion molecule-1 (ICAM-1) expression. The cLABL peptide has been previously demonstrated to possess high avidity for ICAM-1 receptors on the cell surface. Poly(DL-lactic-co-glycolic acid) nanoparticles conjugated with polyethylene glycol and cLABL demonstrated rapid binding to HUVEC with upregulated ICAM-1, which was induced by treating cells with the proinflammatory cytokine, interferon-γ. Binding of the nanoparticles could be efficiently blocked by pre-incubating cells with free peptide suggesting that the binding of the nanoparticles is specifically mediated by surface peptide binding to ICAM-1 on HUVEC. The targeted nanoparticles were rapidly endocytosed and trafficked to lysosomes to a greater extent than the untargeted PLGA-PEG nanoparticles. Verification of peptide-mediated nanoparticle targeting to ICAM-1 may ultimately lead to targeting therapeutic agents to inflammatory sites expressing upregulated ICAM-1.

PLGA nanoparticle-mediated delivery of tumor antigenic peptides elicits effective immune responses

“…Poly(DL-lactide-co-glycolide) (PLGA) is a copolymer that allows controlled release of drug over time or in response to a biological cue. 15 PLGA has many advantages over other polymers used in drug and gene delivery including biodegradability, biocompatibility, and approval for human use granted by the US Food and Drug Administration (FDA). 16 We have successfully delivered plasmid DNA, [17][18][19] drugs, 13,19,20 and peptides 21 by using PLGA-NPs in our previous work.…”

A Fibrinogen-Derived Peptide Provides Intercellular Adhesion Molecule-1-Specific Targeting and Intraendothelial Transport of Polymer Nanocarriers in Human Cell Cultures and Mice

“…Most of these peptides have also been developed and tested in the context of blocking ICAM-1-mediated adhesion during inflammation and cancer metastasis and have been shown to bind to human ICAM-1 but have not been tested in other species. Arguably, the most interesting example of such a peptide from the perspective of targeting drug delivery systems to ICAM-1 is cLABL, which has been shown to provide efficient binding to human epithelial and endothelial cells (Zhang et al, 2008;Chittasupho et al, 2009). The species cross-reactivity of this peptide, en- Fig.…”

The Development of Targeted Drug Delivery Systems for Rheumatoid Arthritis Treatment

“…As indicated by the feasibility of passive targeting, neovascularization is a critical component of rheumatoid arthritis pathogenesis (Szekanecz & Koch, 2008). Adhesion molecules, including intercellular cell-adhesion molecule-1 (ICAM-1) and E-selectin, are upregulated within the newly formed vasculature and; therefore, the endothelium serves as another possibility for active targeting (Banquy et al, 2008;Zhang et al, 2008). Preliminary studies demonstrated that a large number of PLGA-PEG nanoparticles surface modified with a peptide specific for ICAM-1 were endocytosed by vascular endothelial cells as compared to unmodified particles (Zhang et al, 2008).…”

“…Adhesion molecules, including intercellular cell-adhesion molecule-1 (ICAM-1) and E-selectin, are upregulated within the newly formed vasculature and; therefore, the endothelium serves as another possibility for active targeting (Banquy et al, 2008;Zhang et al, 2008). Preliminary studies demonstrated that a large number of PLGA-PEG nanoparticles surface modified with a peptide specific for ICAM-1 were endocytosed by vascular endothelial cells as compared to unmodified particles (Zhang et al, 2008). A similar phenomenon was observed for polyester-based polymeric nanoparticles labeled with ligand specific for E-selectin (Banquy et al, 2008).…”