Nanotechnology Approach for Inhalation Treatment of Pulmonary Fibrosis Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and often fatal form of interstitial lung disease often resulting in patient morbidity and mortality. However, treatment of IPF represents a major clinical challenge since this disorder does not have reliable therapeutic options. Prostaglandin E2 (PGE2), a cyclooxygenase-derived lipid mediator, has attracted considerable attention for its role in the development and progression of IPF and as a possible therapeutic agent for limitation of the immune-inflammatory response, inhibition of specific lung fibroblast functions, their proliferation and synthesis of matrix proteins such as collagen. However, the major challenge in the use of PGE2 for treatment of IPF is its inefficient delivery to the lungs and severe adverse side effects on other organs. To verify that PGE2 can be successfully used for treatment of IPF, we delivered liposomal form of PGE2 via inhalation to the mice with IPF and found that local delivery of PGE2 has a high therapeutic potential. The effect of PGE2 was related to the normalization of the expression of major proteins responsible for the IPF. However, not all targeted proteins were effectively suppressed and some signs of IPF (most notably interstitial lung edema, inflammation, and excessive collagen production) were not completely eliminated. Based on these observations, we hypothesize that the success in the treatment outcome of IPF might be enhanced by combinatorial local lung delivery of PGE2 and suppressors of proteins responsible for inflammation, extracellular matrix degradation, and hypoxic damage. Consequently, the major goal of this study is to develop and test in vivo a specially designed for inhalation nanocarrier-based drug delivery system (DDS) containing PGE2 and siRNA targeted to matrix metalloproteinase (MMP3), chemokine (CCL12) and hypoxia inducible factor one alpha (HIF1A). The proposal is focused mainly on the (1) synthesis and characterization of nanostructured lipid carrier (NLC) for a pulmonary delivery of PGE2 and siRNA; (2) identification of most important proteins involved in the development of IPF; (3) selection of siRNA sequences; (4) characterization and optimization of nanoparticles aerosolization, including optimization of nebulizer performance, determination of airborne DDS concentration, analysis of dynamic stability of DDS; (5) determination of body distribution of delivered DDS in vivo; and (6) evaluation of therapeutic efficiency of the proposed therapeutic approach in a mouse model of IPF (intratracheal administration of bleomycin). The planned research addresses critical problems in treatment of IPF - low effectiveness of therapy and severe adverse side effects. The application performs proof-of-concept experiments of a novel nanotherapeutic strategy for simultaneous local lung delivery of PGE2 and siRNA - suppressors of proteins primarily responsible for inflammation, extra cellular matrix degradation, and hypoxic damage. The project proposes an innovative approach and methodology for the practical realization of this concept.

Public Health Relevance

Pulmonary fibrosis is a chronic, progressive and often fatal form of lung disease for which there is currently not reliable and effective therapy. The project proposes an innovative approach and nanotechnology-based methodology for the inhalation treatment of pulmonary fibrosis. Consequently, the proposed research is highly relevant to public health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL118312-03
Application #
8989150
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Eu, Jerry Pc
Project Start
2014-01-01
Project End
2017-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
3
Fiscal Year
2016
Total Cost
$463,280
Indirect Cost
$158,680
Name
Rutgers University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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Garbuzenko, Olga B; Winkler, Jennifer; Tomassone, M Silvina et al. (2014) Biodegradable Janus nanoparticles for local pulmonary delivery of hydrophilic and hydrophobic molecules to the lungs. Langmuir 30:12941-9
Shah, Vatsal; Taratula, Oleh; Garbuzenko, Olga B et al. (2013) Targeted nanomedicine for suppression of CD44 and simultaneous cell death induction in ovarian cancer: an optimal delivery of siRNA and anticancer drug. Clin Cancer Res 19:6193-204
Taratula, Oleh; Kuzmov, Andriy; Shah, Milin et al. (2013) Nanostructured lipid carriers as multifunctional nanomedicine platform for pulmonary co-delivery of anticancer drugs and siRNA. J Control Release 171:349-57
Ivanova, Vera; Garbuzenko, Olga B; Reuhl, Kenneth R et al. (2013) Inhalation treatment of pulmonary fibrosis by liposomal prostaglandin E2. Eur J Pharm Biopharm 84:335-44