Exosomes were originally thought of as the cellular ?waste-disposal system.? It is now known that they are important for intercellular communication and contribute to the pathogenesis of several diseases including cancer, neurodegenerative disease, and autoimmunity. Once secreted from parental cells, exosomes can be: (a) captured by neighboring cells, and/or (b) released into the systemic circulation for uptake by distant tissues and organs. Thus, their effects are not only local but can have far reaching systemic consequences. For example, cancer invasion and metastasis are promoted by exosomes and their contents. Currently, no therapeutic strategies exploit pathological crosstalk between cells to interrupt disease progression; most therapies target intracellular signaling. The goal of this proposal is to design and synthesize RNA EXO-Codes that are selectively enriched in exosomes. These will be used to: (i) deliver therapeutic RNAs that will reprogram pathological exosomes in vitro and in vivo, and (ii) elucidate mechanisms of nucleic acid sorting to exosomes. Successful completion of this research will result in a platform of zip-code-like biomaterials capable of selectively loading therapeutic cargo into exosomes. This will lay the foundation for the development of a novel therapeutic strategy, based on the hijacking of exosomal sorting machinery, for treating diseases in which exosomes are pathological.

Public Health Relevance

The goal of the proposal is to develop efficient drug carriers capable of intercepting pathological exosomal communication in cancer and other diseases. Specifically, we have synthesized zip code-like biomaterials that are able to selectively deliver therapeutic cargo to exosomes. This approach should allow us to reprogram pathological exosomes and thus halt disease progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
3R01EB023262-02S1
Application #
9722708
Study Section
Program Officer
Rampulla, David
Project Start
2017-08-01
Project End
2020-04-30
Budget Start
2018-09-20
Budget End
2019-04-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
038633251
City
Amherst
State
NY
Country
United States
Zip Code
14228
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Ferguson, Scott; Kim, Sera; Lee, Christine et al. (2018) The Phenotypic Effects of Exosomes Secreted from Distinct Cellular Sources: a Comparative Study Based on miRNA Composition. AAPS J 20:67
Deci, Michael B; Ferguson, Scott W; Scatigno, Sydney L et al. (2018) Modulating Macrophage Polarization through CCR2 Inhibition and Multivalent Engagement. Mol Pharm 15:2721-2731
Wang, Jinli; Seo, Min Jeong; Deci, Michael B et al. (2018) Effect of CCR2 inhibitor-loaded lipid micelles on inflammatory cell migration and cardiac function after myocardial infarction. Int J Nanomedicine 13:6441-6451