Pulmonary Delivery of Recombinant Human Bleomycin Hydrolase Using Mannose-Modified Hierarchically Porous UiO-66 for Preventing Bleomycin-Induced Pulmonary Fibrosis.

ABSTRACT

Bleomycins (BLMs) are widely used in clinics as antitumor agents. However, BLM-based chemotherapies often accompany severe pulmonary fibrosis (PF). Human bleomycin hydrolase is a cysteine protease that can convert BLMs into inactive deamido-BLMs. In this study, mannose-modified hierarchically porous UiO-66 (MHP-UiO-66) nanoparticles (NPs) were used to encapsulate the recombinant human bleomycin hydrolase (rhBLMH). When rhBLMH@MHP-UiO-66 was intratracheally instilled into the lungs, the NPs were transported into the epithelial cells, and rhBLMH prevented the lungs from PF during BLM-based chemotherapies. Encapsulation of rhBLMH in the MHP-UiO-66 NPs protects the enzyme from proteolysis in physiological conditions and enhances cellular uptake. In addition, the MHP-UiO-66 NPs significantly enhance the pulmonary accumulation of intratracheally instilled rhBLMH, thus providing more efficient protection of the lungs against BLMs during the chemotherapies.