Biomedical Engineering Reference
In-Depth Information
and the control formulation. As rapamycin demonstrates acute
neurotoxicity, it is worthwhile to note its significant decrease in the
brain with PEO-PCL micelles. Also important to the administration
of micelle-delivered drugs is the fate of the micelle.
3.3.3.1
Fate of PEO-PCL micelles
in vivo
To prevent a burst release
in vivo
, it is important that the micelles
are stable. The equilibrium between unimers and micelles
in vivo
as well as the CMC are necessary to understand the proper polymer
concentration administered. Liu
et al.
have evaluated this equilibrium
for PEO-PCL micelles in Balb/C mice [17]. Three PEO-PCL micelles
with a constant PCL block length of 5 kDa and PEO block lengths of
2, 5, 10 kDa were evaluated. The PEO-PCL with a PEO block length of
5 kDa was the most stable retaining a monomodal size distribution
according to DLS at physiological conditions with 4.5% BSA over
10 days. PEO-PCL copolymers were incubated with mouse plasma
for 5 h and 37°C at concentrations an order of magnitude below the
CMC. No significant interactions between the plasma and micelles
were found. Tritium labeled [
3
H] PEO-PCL micelles were injected
into the tail vein of Balb/C mice and samples were analyzed via a
scintillation counter. At copolymer concentrations 70-fold above the
CMC (250 mg/kg, upon dilution in the mice), 74% of the micelles
were intact in the plasma after 24 h according to gel filtration
chromatography. At copolymer concentrations 2-fold below the
CMC (2 mg/kg upon dilution), 55% of the micelles remained intact
after 24 h. The tissue distribution of PEO-PCL at 250 mg/kg and 2
mg/kg remained at approximately 10% of the initial dose for each
concentration in the liver through 48 h. Other tissue distribution
studies of PEO-PCL micelles have noted the increased uptake in the
liver due to their size being less than 70 nm [81]. Between 1% and
5% of the initial dose was retained in the heart, kidney, spleen, and
lung through 48 h for the same doses. However when 0.2 mg/kg
PEO-PCL was administered, the accumulation in the liver rose from
10% of the initial dose to approximately 40% through 48 h. Between
5% and 10% of the initial dose remained in the heart, kidney, spleen,
and lung through 48 h. The higher retention of this dose (0.2 mg/
kg) in organs may be a reflection of the pharmacokinetics. At 0.2
mg/kg, the PEO-PCL micelle was rapidly cleared from the plasma
in approximately 12 h. However, the 2 mg/kg dose wasn't cleared
from the plasma until 50 h, and the 250 mg/kg dose had 20% of
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