It has been recognized for decades that lipid-encapsulated cellular material is present in human blood, and that these particles can affect coagulation and stability. Although these """"""""microparticles"""""""" have been traditionally thought to be cellular debris, more recent studies have demonstrated that a fraction of very small particles (30-100 nm) are produced by tumors and comprise a novel communication network among tumor cells. These small vesicles are termed """"""""exosomes"""""""", and studies have shown that tumor exosomes are programmed to transfer active biomolecules (RNA, proteins) to specific sites in vivo and have been implicated in metastasis. Recent in vivo studies have reported that exosomes offer significant advantages over synthetic drug delivery systems including enhanced serum stability, low immunogenicity, and minimal clearance by lung, liver, and spleen. In addition to these beneficial characteristics, our preliminary data indicate that exosomes from tumor cells are taken up to a much greater extent by the parent tumor cell type as compared to other cell lines. This """"""""homing"""""""" is not due to an inherently greater capacity for non-specific uptake, and the proposed studies further characterize this effect as well as investigate the protein and lipid components that are responsible for this tropism. The ability of tumor exosomes to home to the parent tumor in a mouse model will be quantified with PET imaging, and the tumor-homing behavior will be exploited by utilizing exosomes to deliver chemotherapeutics in tumor-bearing mice. Using the information gathered from proteomic and lipidomic analyses, the work also explores the potential of developing a synthetic vesicle containing the components that endow exosomes with their ability to home to tumors.

Public Health Relevance

The presence of small vesicles in cancer patient serum has recently been shown to correlate with the stage of disease, which has unveiled a previously unknown network of communication and transportation among cancer cells. It follows that these same vesicles might be harnessed and exploited to deliver chemotherapeutics specifically to tumors, thereby minimizing side effects and potentially overcoming drug resistance. The proposal investigates this hypothesis in tumor-bearing mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB016378-02
Application #
8706865
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Tucker, Jessica
Project Start
2013-08-01
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
$375,976
Indirect Cost
$133,476
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Graner, Michael W; Schnell, Sathya; Olin, Michael R (2018) Tumor-derived exosomes, microRNAs, and cancer immune suppression. Semin Immunopathol 40:505-515
Betker, Jamie L; Anchordoquy, Thomas J (2017) Assessing the effect of a nude mouse model on nanoparticle-mediated gene delivery. Drug Deliv Transl Res 7:162-167
Betker, Jamie L; Anchordoquy, Thomas J (2017) Nonadditive Effects of Repetitive Administration of Lipoplexes in Immunocompetent Mice. J Pharm Sci 106:872-881
Anchordoquy, Thomas J; Simberg, Dmitri (2017) Watching the gorilla and questioning delivery dogma. J Control Release 262:87-90
Graner, Arin N; Hellwinkel, Justin E; Lencioni, Alex M et al. (2016) HSP90 inhibitors in the context of heat shock and the unfolded protein response: effects on a primary canine pulmonary adenocarcinoma cell line. Int J Hyperthermia :1-15
Redzic, Jasmina S; Gomez, Joe D; Hellwinkel, Justin E et al. (2016) Proteomic analyses of brain tumor cell lines amidst the unfolded protein response. Oncotarget 7:47831-47847
Hellwinkel, Justin E; Redzic, Jasmina S; Harland, Tessa A et al. (2016) Glioma-derived extracellular vesicles selectively suppress immune responses. Neuro Oncol 18:497-506
Graner, Michael W (2016) HSP90 and Immune Modulation in Cancer. Adv Cancer Res 129:191-224
Smyth, Tyson; Kullberg, Max; Malik, Noeen et al. (2015) Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. J Control Release 199:145-55
Kunigelis, Katherine E; Graner, Michael W (2015) The Dichotomy of Tumor Exosomes (TEX) in Cancer Immunity: Is It All in the ConTEXt? Vaccines (Basel) 3:1019-51

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