Biomedical Engineering Reference
In-Depth Information
them
without
disrupting
other
immune
functions
remained
44
challenging.
To inhibit the function of this particular subset,
C12-200 was complexed with siRNA targeting chemokine receptor
2 (CCR2), a protein critical in their recruitment.
CCR2 mediates
inflammatory monocyte behavior but does not have a functional role
in noninflammatory monocytes.
40
40
Since the spleen, bone marrow, and blood are rich in monocytes,
members of our lab quantified real-time biodistribution of
C12-200 in multiple organs. After complexation with fluorescently
tagged siRNA, particles were tracked using fluorescence molecular
tomography and computed tomography (FMT-CT) imaging.
45
siRNA
concentration was highest in the monocyte-rich spleen and bone
marrow for the first 24 hours following intravenous injection of
1 mg/kg siRNA. Subsequent histological staining and FACS analyses
demonstrated that C12-200 transfected inflammatory monocytes
more efficiently than other immune cell types. Once delivery to
inflammatory monocytes was confirmed, 50% mRNA silencing and
reduced protein expression was measured following intravenous
injection of 0.5 mg/kg CCR2 siRNA.
By inhibiting inflammatory monocyte recruitment through CCR2
silencing, the authors sought to mitigate inflammatory responses
in myocardial infarctions, pancreatic islet transplant rejection, and
lymphoma. Since activated macrophages and other inflammatory
cells lead both to plaque rupture and increased infarct size once a
heart attack occurs, the authors sought to reduce their accumulation
in plaques.
46, 47
Both macrophage accumulation and infarct size were
measured after control or CCR2 siRNA was injected intravenously
into mice at a dose of 0.5 mg/kg. Excitingly, both parameters were
markedly reduced relative to controls. The authors also investigated
whether CCR2 silencing would promote islet transplantation.
Although islet transplantation has been successful in treating
diabetes, grafts are often rejected by the host immune system.
48
After intravenous injection of lipidoids containing CCR2 siRNA at a
dose of 0.5 mg/kg, graft survival was enhanced, leading to improved
glycemic performance.
Finally, the authors examined whether CCR2 prompted the
recruitment of tumor-associated macrophage (TAMs). TAMs
promote tumor growth and metastasis via the release of matrix
metalloproteinases (MMPs) and other molecules that degrade
extracelluar matrix, releasing growth factors and clearing a path
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