Browsing by Subject "exosomes"

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    Signaling Extraordinaire: Extracellular vesicles in cranial neural crest migration
    (2022-05) Gustafson, Callie
    Extracellular vesicles (EVs) are membrane-bound particles released from all cells that have thus far been examined. Commonly studied in cancer biology, many categories of EVs have been characterized. EVs serve as a means of cell-cell communication across short and long distances. Cells also extend membranous protrusions to communicate and connect with distant cells, and developmental studies show they can serve as highways or conduits for the transfer of EVs. While cancer biology often lacks the context of a physiological system, developmental biology struggles to properly characterize EVs and protrusions. Neural crest cells (NCC) are an ideal system for bridging these fields because invasive cancer reactivates neural crest developmental programs, including epithelial to mesenchymal transition (EMT) and migration. Using cranial neural fold cultures, we identify two types of NCC-derived EVs: exosomes and migrasomes. Upon inhibition of exosome secretion, NCC migration is disrupted, leading to rounder, less motile cells. This data suggests NCC exosomes are critical for migration.
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    Targeting Tumor-Associated Macrophages with PI3Kγ Inhibitor-loaded Nanocarriers for Cancer Therapy
    (2020-12) Wang, Yihan
    AbstractMacrophages exist in virtually all organs and are central players in normal immune functions. They are also key regulators in the pathogenesis of various human diseases, including cancer. Once in tumors, these cells can adopt a tumor-promoting phenotype named tumor-associated macrophages (TAMs). TAMs contribute to tumor growth in many ways, such as immunosuppression, angiogenesis, and metastasis. [1] PI3Kγ is a signal-transducing enzyme that mediates the key cellular functions in cancer and immunity. It is highly expressed in TAMs and plays an important role in the pro-tumor function of these cells. Inhibit its activity can lead to the expression of pro-inflammatory factors, then stimulate cytotoxic T cell activation, anti-tumor immunity, and promote tumor regression.[2] IPI549 is a potent and highly selective inhibitor of PI3kγ. It can repolarize TAMs toward a pro-inflammatory phenotype, which suppresses tumor growth. It also demonstrates robust inhibition of PI3K-γ mediated neutrophil migration in-vivo. [3] CRV is a macrophage-targeting peptide. It can specifically bind to the RXRB receptor, which expresses in TAMs. After systemic administration, rapid and efficient homing of CRV to the TAMs can be observed. [4] Since the PI3kγ expressed in both tumor and healthy tissues, CRV could be utilized as the ligand, which specifically targeting to TAMs and concentrates the IPI549 at TAMs. Due to the low solubility and potential side effects of IPI549, nanocarriers (liposomes and exosomes) which are decorated with CRV peptide, are utilized to load IPI549. It was expected to enhance the specific uptake of the compound by TAMs in-vivo. Methods and Results Two strategies were used to enhance the loading efficiency. First, 1, 2-Distearoyl-sn-glycero-3-phosphoethanolamine-Poly(ethylene glycol) (DSPE-PEG2000) and Egg phosphatidylcholine (EPC) were used to build the phospholipid bilayer. The unsaturated and saturated phosphatidylcholines, with a significant difference in phase transition temperature and chain stiffness, created bilayer "pockets" in which the bulky IPI549 is embedded. Meanwhile, DSPE-PEG2000 micelles encapsulate IPI549 in a hydrophobic cavity, then fusion with the phospholipid bilayer of liposomes further increases the drug loading. Exosomes secreted by RAW cells were isolated and collected by ultra-centrifuging. CRV was decorated on the surface of nanocarriers (exosomes and liposomes) through incubation methods. Conclusion 25% IPI549 to phospholipid molar ratio, a relatively high drug loading compared to other insoluble drugs, was attained during liposome preparation. After systemic administration, rapid and efficient homing of CRV-IPI549 liposomes to the tumors could be observed. The decorated ligands（TAT and RPAR）of the exosomes still keep the combination activity with their receptors (heparin and neuropilin 1 receptor b1b2 domain protein). The decorated ligands do not inhibit the uptake of exosomes by macrophages. Keywords: TAM; PI3Kγ inhibitor; CRV peptide; liposomes; exosomes.