ICAM-1 targeting, intracellular trafficking, and functional activity of polymer nanocarriers coated with a fibrinogen-derived peptide for lysosomal enzyme replacement

Abstract

Enzyme replacement is a viable treatment for diseases caused by genetic deficiency of lysosomal enzymes. However, suboptimal access of enzymes to target sites limits this strategy. Polymer nanocarriers (NCs) coated with antibody against intercellular adhesion molecule 1 (ICAM-1), a protein overexpressed on most cells under disease states, enhanced biosdistribution and lysosomal delivery of these therapeutics. Whether this can be achieved using more biocompatible ICAM-1-targeting moieties is unknown, since intracellular uptake via this route is sensitive to the receptor epitope being targeted. We examined this using polymer NCs coated with an ICAM-1-targeting peptide derived from the fibrinogen sequence. Scrambled-sequence peptide and anti-ICAM were used as controls. NCs carried acid sphingomyelinase (ASM), used for treatment of type B Niemann-Pick disease, and fluorescence microscopy was employed to examine cellular performance. Peptide-coated/enzyme NCs efficiently targeted ICAM-1 (22-fold over non-specific counterparts; Bmax ~180 NCs/cell; t1/2 ~28 min), recognized human and mouse cells (1.2- to 0.7-fold binding vs. antibody/enzyme NCs), were efficiently endocytosed (71% at 1 h chase), and trafficked to lysosomes (30-45% of internalized NCs; 2 h chase). This restored lysosomal levels of sphingomyelin and cholesterol within 5 h chase (~95% of disease levels), similar to antibody-enzyme NCs. This fibrinogen-derived ICAM-1-targeting peptide holds potential for lysosomal enzyme replacement therapy.

Plasmolipin regulates basolateral-to-apical transcytosis of ICAM-1 and leukocyte adhesion in polarized hepatic epithelial cells

“…It is thus reasonable that the machinery interacting and transporting ICAM-1 to specific cell surface domains participates in the organization of these plasma membrane domains [10]. Intracellular ICAM-1 trafficking has not been addressed in detail other than as a receptor for functional nanocarriers for drug delivery [37] or as a receptor for rhinovirus [38], despite the receptor relevance in the inflammatory response, and no proximal interaction of ICAM-1 with polarized intracellular trafficking machinery had previously been reported. In TNF-stimulated endothelial cells, ICAM-1 undergoes apical-to-basolateral transcytosis through caveola upon engagement, which regulates leukocyte diapedesis [30].…”

“…ICAM-1 was basolaterally labeled (BL-ICAM-1) with a specific antibody at 4 °C in HepG2 cells (0 min). Cells were then incubated at37 °C for 90 min. Single channels from the squared area are individually shown in greyscale on the right images.…”

Recent advance in treatment of atherosclerosis: Key targets and plaque-positioned delivery strategies

“…Peptide ligands decoration for binding to ICAM-1, such as fibrinogen-derived peptide (NNQKIVNLKEKVAQLEA) and the sequence VHPKQHR, yielded a specific and high-affinity system directing to inflamed endothelial surface in atherosclerotic lesions. 24 , 25 For orientating atheroma, superfluous VCAM-1 can straight tether ligand-modified objects to lesional site, and these ligands included specific antibody or some peptides, like anti-VCAM-1 antibody, anti-VCAM-1 nanobody, and VHSPNKK. 26 – 28 The ligand with VHSPNKK sequence also blocked leukocyte-endothelium interactions.…”

Strategies for Enhancing the Permeation of CNS-Active Drugs through the Blood-Brain Barrier: A Review

“…Several works exploring targeting of ICAM-1 have been reported in the literature [ 80 , 81 ]. In a work by Garancho and Muro [ 82 ], polymer nanocarriers coated with ICAM-1 targeting peptide were examined. Prepared nanocarriers were endocytosed and trafficked to lysosomes, restoring levels of sphingomyelin and cholesterol within lysosomes.…”