Researchers found that enzyme replacement therapy (ERT) using nanoparticles to encapsulate the enzymes resulted in the best delivery to the tissue in lysosomal storage disorders such as Pompe disease (PD), as published in the International Journal of Molecular Sciences.
Muntimadugu and colleagues tested the delivery of hyaluronidase by independently studying and later comparing 3 groups: the first group consisted of only the free enzyme, and the second included the poly(lactide-glycolide) (PLGA) nanoparticles coated in the enzyme, and the third contained nanoparticles encapsulating the hyaluronidase.
Both methods using nanoparticles achieved better delivery than the free drug. Overall, the encapsulated enzyme was superior, with an 18.4-fold enhancement in cells and 6.2-fold enhancement in the brain, while the coated nanoparticles showcased 4.3- and 3-fold enhancements in the respective targets.
“While said improvement is observed for both enzyme encapsulated and coated PLGA formulations, the former preparations are superior because of their enhanced enzyme load per [nanoparticles] and, likely, lack of interference with the targeting antibody coat,” the authors said. “These formulations hold considerable potential to advance lysosomal ERTs.”
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Although the enzyme deficient in PD is acid α-glucosidase and not hyaluronidase, these findings remain relevant to this clinical entity. Patients with PD have widely benefited from ERT, and enhanced enzyme delivery has been previously reported using similar techniques, including oral presentations that included anti-intercellular adhesion molecule-1 nanoparticles in microcapsules to protect the enzyme from gastric secretions.
In vivo, the brain and other organs yielded promising results with this technique, and the blood-brain barrier and neural, skeletal muscle, and endothelial cells have demonstrated the same success in vitro.
Even though these formulations propose important benefits, specific enzyme activity does decrease when compared to the free form. Additionally, because lysosomal enzymes are active only at an acidic pH, the neutral condition of nanoparticles may prevent premature activation before reaching the target tissue.
“We observed that the number of [hyaluronidase]-positive [nanoparticles] colocalizing with anti-[intercellular adhesion molecule] decreased around 25% between 1 h and 3 h (not shown),” the authors said. “This result suggested lysosomal trafficking of this formulation, its intended destination.”
Muntimadugu E, Silva-Abreu M, Vives G, et al. Comparison between nanoparticle encapsulation and surface loading for lysosomal enzyme replacement therapy. Int J Mol Sci. 2022;23(7):4034. doi:10.3390/ijms23074034