title: Hyaluronidase-loaded PLGA microparticles as a new strategy for the treatment of pulmonary fibrosis.
abstract: The aim of this work was to develop an innovative tool for the treatment of pulmonary fibrosis based on our previous findings, which demonstrated that intranasally administered soluble bovine hyaluronidase (HYAL) increases the numbers of mesenchymal (MSC)-like cells in the bronchoalveolar fluid (BALF) and thus reduces the bleomycin-induced fibrosis. To this end, we developed poly(D,L-lactide-co-glycolide) (PLGA) microparticles (MPs) loaded with HYAL (HYAL-MP) to preserve the enzyme's biological activity and to facilitate its delivery to the lung. Nonloaded MPs (Control-MPs) and HYAL-MPs were prepared using the emulsion and solvent evaporation methods and thoroughly characterized. The HYAL-MPs and Control-MPs exhibited an average diameter of 4.3±2.1 and 4.4±1.5 μm, respectively. The encapsulation efficiency of the HYAL-MPs was 68%, and encapsulation led to a reduced release rate. Additionally, the HYAL-MPs were efficiently phagocytosed by J-774.1 cells. Compared with the soluble HYAL, the HYAL-MPs increased the proportion of MSC-like cells in the BALF of C57BL6 mice 96 h after treatment. The efficacy of the HYAL-MPs was also tested in C57BL6 mice that were previously exposed to 4 U/kg of bleomycin to induce lung fibrosis. The results demonstrated that the HYAL-MPs reduced neutrophil recruitment after bleomycin treatment more effectively than did the soluble HYAL, whereas the Control-MPs did not exhibit any effect. The HYAL-MPs also reduced the bleomycin-induced fibrosis more efficiently, and 134% of the collagen deposition in the lung compared with the soluble HYAL and the Control-MPs. In summary, our data indicate that HYAL-MPs are an effective delivery system that could feasibly be used in the treatment of pulmonary fibrosis.
authors.affiliation: 1 Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo ,- Ribeirão Preto, Brazil .
authors.forename: Claudia
authors.initials: C
authors.lastname: da Silva Bitencourt
authors.forename: Guilherme Martins
authors.initials: GM
authors.lastname: Gelfuso
authors.forename: Priscilla Aparecida Tartari
authors.initials: PA
authors.lastname: Pereira
authors.forename: Patrícia Aparecida
authors.initials: PA
authors.lastname: de Assis
authors.forename: Cristiane
authors.initials: C
authors.lastname: Tefé-Silva
authors.forename: Simone Gusmão
authors.initials: SG
authors.lastname: Ramos
authors.forename: Eliane Candiani
authors.initials: EC
authors.lastname: Arantes
authors.forename: Lúcia Helena
authors.initials: LH
authors.lastname: Faccioli
mesh_terms: D000818:Animals; D002417:Cattle; D002452:Cell Count; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D006821:Hyaluronoglucosaminidase / Q000627:therapeutic use*; D019344:Lactic Acid / Q000737:chemistry*; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D010316:Particle Size; D010586:Phagocytes / Q000166:cytology; D011014:Pneumonia / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011658:Pulmonary Fibrosis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D055672:Static Electricity; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D003094:Collagen; D006821:Hyaluronoglucosaminidase