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 biodistribution 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; B_max ∼180 NCs/cell; t_1/2 ∼28 min), recognised 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 internalised NCs; 2 h chase). This restored lysosomal levels of sphingomyelin and cholesterol within 5 h chase (∼95% reduction over disease levels), similar to antibody-enzyme NCs. This fibrinogen-derived ICAM-1-targeting peptide holds potential for lysosomal enzyme replacement therapy.

Keywords:

• ICAM-1 targeting
• fibrinogen-derived peptide
• polymer nanocarriers
• enzyme replacement therapy
• lysosomal storage diseases
• Niemann–Pick disease
• acid sphingomyelinase

Acknowledgements

The authors thank Dr. Edward Schuchman (Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY) for providing recombinant human ASM and NPD fibroblasts, and Dr. Melani Solomon and Mr. Niksa Roki (Fischell Department of Bioengineering, University of Maryland, College Park, MD) for technical assistance.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by National Institutes of Health award R01-HL98416 and National Science Foundation award CBET-1402756 (to S.M.).