Enhanced delivery of α-glucosidase for Pompe disease by ICAM-1-targeted nanocarriers: comparative performance of a strategy for three distinct lysosomal storage disorders

doi:10.1016/j.nano.2011.08.014

Nanomedicine: Nanotechnology, Biology and Medicine

Volume 8, Issue 5, July 2012, Pages 731-739

https://doi.org/10.1016/j.nano.2011.08.014 Get rights and content

Abstract

Enzyme replacement therapies for lysosomal storage disorders are often hindered by suboptimal biodistribution of recombinant enzymes after systemic injection. This is the case for Pompe disease caused by acid α-glucosidase (GAA) deficiency, leading to excess glycogen storage throughout the body, mainly the liver and striated muscle. Targeting intercellular adhesion molecule-1 (ICAM-1), a protein involved in inflammation and overexpressed on most cells under pathological conditions, provides broad biodistribution and lysosomal transport of therapeutic cargoes. To improve its delivery, we coupled GAA to polymer nanocarriers (NCs; ∼180 nm) coated with an antibody specific to ICAM-1. Fluorescence microscopy showed specific targeting of anti-ICAM/GAA NCs to cells, with efficient internalization and lysosomal transport, enhancing glycogen degradation over nontargeted GAA. Radioisotope tracing in mice demonstrated enhanced GAA accumulation in all organs, including Pompe targets. Along with improved delivery of Niemann-Pick and Fabry enzymes, previously described, these results indicate that ICAM-1 targeting holds promise as a broad platform for lysosomal enzyme delivery.

From the Clinical Editor

In this study, ICAM-1 targeted nanocarriers were used to deliver GAA (acid alpha glucosidase) into cells to address the specific enzyme deficiency in Pompe’s disease. The results unequivocally demonstrate enhanced enzyme delivery over nontargeted GAA in a mice model.

Graphical Abstract

Anti-ICAM NCs enhanced delivery of α-glucosidase to tissue in mice and increased glycogen degradation in a cell model.

Section snippets

Antibodies and reagents

Monoclonal antibodies specific to human or murine ICAM-1 (anti-ICAM) were R6.5 (Ref. [26]) or YN1 (Ref. [32]). Secondary antibodies were from Jackson Immunoresearch (West Grove, Pennsylvania). Saccharomyces cerevisiae recombinant GAA was from Sigma-Aldrich (St. Louis, Missouri). Polystyrene beads (100 nm diameter) were from Polyscience (Warrington, Pennsylvania). Cell culture reagents were from Cellgro (Manassas, Virginia) or Gibco BRL (Grand Island, New York). Other reagents were from

Characterization of anti-ICAM/GAA NCs and enzyme release

Anti-ICAM and GAA were coated onto 100 nm NCs (anti-ICAM/GAA NCs). As shown in Table 1, the ¹²⁵I-GAA loading efficiency was 86.2 ± 4.3%, giving 277.7 ± 1.4 GAA molecules per carrier and diameter of 180.1 ± 0.9 nm when co-coated at a 50:50 mass ratio (selected based on the enzyme dose estimated to exert biochemical effects6, 7).

The enzyme coat was stable through centrifugation, resuspension by pipetting, and sonication (11.6 ± 0.3% enzyme release), and during storage at 4°C in buffer (0.0 ± 0.1%

Discussion

Our results indicate that ICAM-1 targeting holds potential to improve delivery of GAA for ERT of Pompe disease. Anti-ICAM/GAA NCs provided efficient targeting in Pompe disease model cells and primary cultures of skeletal muscle, as well as internalization and lysosomal transport with attenuation of excess glycogen, surpassing the effects of free GAA. Anti-ICAM/GAA NCs also markedly enhanced enzyme delivery in vivo compared to nontargeted GAA in all tissues tested, including heart, skeletal

Acknowledgments

The authors thank Edward Lim and Dave Dolak (Malvern Instruments, Westborough, Massachusetts) for providing dynamic light scattering size measurement of anti-ICAM/GAA NCs.

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: This work was supported by the National Science Foundation Research Experience for Undergraduates program of the Bioengineering Department in the University of Maryland (L.N.), Nanobiotechnology Program of the Maryland Department of Business and Economic Development, Minta Martin Foundation, AHA 09BGIA2450014, and R01HL098416 (S.M.).

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Research ArticleEnhanced delivery of α-glucosidase for Pompe disease by ICAM-1-targeted nanocarriers: comparative performance of a strategy for three distinct lysosomal storage disorders

Abstract

From the Clinical Editor

Graphical Abstract

Section snippets

Antibodies and reagents

Characterization of anti-ICAM/GAA NCs and enzyme release

Discussion

Acknowledgments

Neuromuscul Disord

Biochem Biophys Res Commun

Neurotherapeutics

Mol Genet Metab

Mol Genet Metab

Mol Genet Metab

Am J Hum Genet

Mol Ther

J Control Release

Mol Ther

Mol Ther

Cell

Kidney Int

J Control Release

Adv Drug Deliv Rev

Clin Chim Acta

J Control Release

The cell biology of lysosomal storage disorders

Nat Rev Mol Cell Biol

Glycogen storage disease type II: acid α-glucosidase (acid maltase) deficiency

Autophagy in skeletal muscle: implications for Pompe disease

Int J Clin Pharmacol Ther

Research Article
Enhanced delivery of α-glucosidase for Pompe disease by ICAM-1-targeted nanocarriers: comparative performance of a strategy for three distinct lysosomal storage disorders