Valsartan Loaded Micelle for Th2 High Lung Disease Management
Embargo until
2023-05-01
Date
2021-05-11
Authors
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Journal ISSN
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Publisher
Johns Hopkins University
Abstract
Th-2 high lung disease is a family of highly heterogenous diseases, in which the type 2 lymphoid cells are stimulated to release Th2 cytokines (e.g. IL-13 and IL-4) and activate type 2 inflammation, facilitating the disease develop to an uncontrolled stage. The management and symptoms reversing of uncontrolled Th2 high lung disease still remain highly problematic, despite inhaled corticosteroids (ICSs) and several add-on therapeutics were selected as the current clinical medication. Here, we developed an inhalable valsartan loaded micelle (TW80/Val) to reverse the nature history of Th2 high lung disease in an inducible CC10-rtTA-IL-13 mice model. TW80/Val was formulated by simply mixing an angiotensin receptor blocker (ARB), valsartan, and a FDA approved inhalable excipient, Tween 80, and can be stored as low-endotoxin dry powder after lyophilization. TW80/Val performs a efficient pulmonary delivery due to its mucus penetrating property as well as the macrophage-resistance given by the PEGylation of TW80. Then, after applying hypotonic vehicle to further enhance the distribution on airway epithelial cells, we also show the enhanced pulmonary accumulation after intratracheal TW80/Val administration, comparing to dosing with free drug, and demonstrated its promising biosafety, especially for no lifting Th2 immune response. The eventual therapy effect was examined after one-month intratracheal administration with TW80/Val (1 mg/kg) every other day. The histological studies were conducted and revealed that TW80/Val successfully reverse the key pathologic features of severe asthma, including emphysema, Th2 inflammation, mucus hypersecretion and fibrosis. Therefore, our formulation creates a practical option to develop Th2 high lung disease management clinically with the rare-reported symptoms-reversing ability
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Keywords
Lung Disease, Valsartan, Micelle,Th2 Cytokines.