ABSTRACT
Systemic administration of bio-therapeutics can result in only a fraction of drug reaching targeted tissues, with the majority of drug being distributed to tissues irrelevant to the drug's site of action. Targeted delivery to specific organs may allow for greater accumulation, better efficacy, and improved safety. We investigated how targeting plasmalemma vesicle-associated protein (PV1), a protein found in the endothelial caveolae of lungs and kidneys, can promote accumulation in these organs. Using ex vivo fluorescence imaging, we show that intravenously administered αPV1 antibodies localize to mouse lungs and kidneys. In a bleomycin-induced idiopathic pulmonary fibrosis (IPF) mouse model, αPV1 conjugated to Prostaglandin E2 (PGE2), a known anti-fibrotic agent, significantly reduced collagen content and fibrosis whereas a non-targeted PGE2 antibody conjugate failed to slow fibrosis progression. Our results demonstrate that PV1 targeting can be utilized to deliver therapeutics to lungs and this approach is potentially applicable for various lung diseases.
Subject(s)
Drug Carriers , Drug Delivery Systems , Idiopathic Pulmonary Fibrosis/drug therapy , Membrane Proteins/metabolism , Animals , Biomarkers , Bleomycin/adverse effects , Dinoprostone/metabolism , Disease Models, Animal , Gene Expression , Humans , Idiopathic Pulmonary Fibrosis/etiology , Idiopathic Pulmonary Fibrosis/pathology , Immunohistochemistry , Kidney/metabolism , Kidney/pathology , Lung/drug effects , Lung/metabolism , Lung/pathology , Membrane Proteins/chemistry , Membrane Proteins/genetics , MiceABSTRACT
alpha-Galactosidase A is the lysosomal hydrolase that is deficient in patients with Fabry disease. Intravenous infusion of agalsidase alfa, a preparation of alpha-Galactosidase A, is used for enzyme replacement therapy (ERT) in patients with Fabry disease. Although ERT appears to show some beneficial effects, most patients show only a modest response. We investigated using immunohistochemistry the relative tissue and cellular distribution of agalsidase alfa after a single intravenous injection in a mouse knockout model of Fabry disease. Specific immunostaining for agalsidase alfa was found only in liver, kidney, heart, testes, adrenal gland, spleen and bone marrow. There was no difference in distribution of the infused enzyme distribution among tissues sampled 4, 24, and 48h post-injection. The intracellular localization of immunopositivity varied considerably between organs with vascular endothelium being the most commonly positive site. alpha-Galactosidase A specific activity in tissue homogenates matched the relative extent of agalsidase alfa immunostaining distribution in the same organs. We conclude that intravenously injected agalsidase alfa has a very heterogeneous systemic distribution using an immunostaining technique.
