Nanoparticles are emerging tools that will impact medical diagnosis and therapeutics with their capacity to target cells and tissues with imaging agents and/or drug payloads. The unique physical aspects of nanoparticles present new challenges for guidance and regulation. A wide variety of blood contact interactions may compromise intended nanoparticle activities and/or cause serious side effects. The simulation modeling of these and other critical biological interactions would provide a powerful predictive instrument that would offer a focus for the safety review of product candidates and allow the crafting of specific guidelines to be addressed by future applicants. It is known that certain lipid encapsulated nanoparticles activate the complement system, with the potential of severe tissue damage. We propose to develop a standard series of assays to characterize the interactions of complement with lipid encapsulated nanoparticles. The results will be applied to a bioinformatics-modeling system to design and assess next generation nanoparticles for clinical use. Our proposed specific efforts would provide a proof-of-concept approach to study a broad array of nanostructure:biological interactions that are currently difficult to predict prior to human study. To these ends we submit the following specific aims: (1) Develop standardized protocols using human in vitro and mouse In vivo models to characterize the capacity of lipid encapsulated nanoparticles to activate complement, to identify the activation pathways that facilitate the process, and to assess the impact of endogenous complement inhibitors on nanoparticle-dependent complement activation. (2) Vary lipid encapsulated nanoparticles to understand the influence of particle surface characteristics on complement activation. Manipulate surfactant components by utilizing natural and synthetically modified lipids to create a broad spectrum of biochemical presentations at, above, and below water-membrane interface that impart different charge or surface chemical properties. (3) Develop structure-activity relationships to predict complement activation.

Public Health Relevance

Nanoparticles are emerging tools that will impact medical diagnosis and therapeutics but present new challenges for product safety. The goal of this proposal is to construct a method for predicting likely harmful effects of nanoparticles prior to their testing in human subjects. Such a device would offer a focus for safety review of new candidate nanoparticle products and allow the crafting of specific guidelines to be addressed hv future nannnartinip riPRinns

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS073457-02
Application #
8150949
Study Section
Special Emphasis Panel (ZRG1-ETTN-A (50))
Program Officer
Morris, Jill A
Project Start
2010-09-27
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$982,858
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wang, Kezheng; Pan, Dipanjan; Schmieder, Anne H et al. (2015) Synergy between surface and core entrapped metals in a mixed manganese-gadolinium nanocolloid affords safer MR imaging of sparse biomarkers. Nanomedicine 11:601-9
Goette, Matthew J; Keupp, Jochen; Rahmer, J├╝rgen et al. (2015) Balanced UTE-SSFP for 19F MR imaging of complex spectra. Magn Reson Med 74:537-43
Zhang, Ruiying; Pan, Dipanjan; Cai, Xin et al. (2015) alphaVbeta3-targeted copper nanoparticles incorporating an Sn 2 lipase-labile fumagillin prodrug for photoacoustic neovascular imaging and treatment. Theranostics 5:124-33
Wagner, Elizabeth M; Jenkins, John; Schmieder, Anne et al. (2015) Angiogenesis and airway reactivity in asthmatic Brown Norway rats. Angiogenesis 18:1-11
Harper, Bryan; Thomas, Dennis; Chikkagoudar, Satish et al. (2015) Comparative hazard analysis and toxicological modeling of diverse nanomaterials using the embryonic zebrafish (EZ) metric of toxicity. J Nanopart Res 17:250
Pan, Dipanjan; Kim, Benjamin; Hu, Grace et al. (2015) A strategy for combating melanoma with oncogenic c-Myc inhibitors and targeted nanotherapy. Nanomedicine (Lond) 10:241-51
Bulte, Jeff W M; Schmieder, Anne H; Keupp, Jochen et al. (2014) MR cholangiography demonstrates unsuspected rapid biliary clearance of nanoparticles in rodents: implications for clinical translation. Nanomedicine 10:1385-8
Daily, Michael D; Olsen, Brett N; Schlesinger, Paul H et al. (2014) Improved Coarse-Grained Modeling of Cholesterol-Containing Lipid Bilayers. J Chem Theory Comput 10:2137-2150
Pan, Dipanjan; Schmieder, Anne H; Wang, Kezheng et al. (2014) Anti-angiogenesis therapy in the Vx2 rabbit cancer model with a lipase-cleavable Sn 2 taxane phospholipid prodrug using ?(v)??-targeted theranostic nanoparticles. Theranostics 4:565-78
Pham, Christine T N; Thomas, Dennis G; Beiser, Julia et al. (2014) Application of a hemolysis assay for analysis of complement activation by perfluorocarbon nanoparticles. Nanomedicine 10:651-60

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