Biomedical Engineering Reference
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than that of micelles with larger PEO chains. Negative zeta potential
increases the micelles' uptake by macrophages of the mononuclear
phagocyte system [74, 75].
3.3.1
Cellular Internalization of PEO-PCL Micelles
As this macrophage uptake would represent one mode of the
micelles clearance
in vivo
, it is also important to understand how
these micelles interact with other cells. This question has typically
been addressed through the use of fluorescent dyes or radioactive
compounds. Both of these approaches were used to demonstrate
that the cellular uptake of PEO
44
-PCL
20
micelles in a PC 12 cell line
was temperature and pH dependent [76] in a manner indicative of
endocytosis uptake mechanisms. Mahmud
et al.
studied the uptake
of various PEO-PCL micelles with diff erent PCL block lengths in
MCF-7 breast cancer cells [21]. These micelles were loaded with
a lipophilic fluorescent dye, DiI, and the mechanism of endocytic
uptake was investigated with chlorpromazine and cytochalasin B. An
optimal PCL block length of 13 kDa, and PEO block length of 5 kDa
demonstrated the highest cellular uptake. Chlorpromazine is known
to inhibit clathrin-mediated endocytosis by reducing clathrin-coated
pit formation at the cellular membrane, while cytochalasin B inhibits
phagocytosis through disruption of microfilament bundles at the
cell membrane. Both endocytosis inhibiting agents reduced uptake
at the optimal block lengths of PEO and PCL. Incubation of MCF-7
cells at 4°C in the absence of these agents also reduced uptake. This
suggests an energy-dependent uptake mechanism, which further
supports both clathrin-mediated endocytosis and phagocytosis.
3.3.2
Cellular Distribution of PEO-PCL Micelles
Further work investigated the cellular distribution of PEO
45
-PCL
23
micelles with tetramethylrhodamine-5-carbonyl azide (TMRCA)
conjugated to the end of the PCL block in PC 12 and NIH 3T3 cell lines
[77]. Although PEO is known prevent protein adsorption, and had
been shown to reduce uptake of PEO:PLGA nanoparticles in human
monocytes [78], not all of the PEO-PCL micelles were excluded from
these cell lines. Using a series of organelle and nuclear selective dyes,
it was found that PEO-PCL was primarily taken up into cytoplasmic
organelles, specifically the Golgi apparatus and mitochondria. Shuai
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