Biomedical Engineering Reference
In-Depth Information
of release at lower pH in relation to cancer therapy because tumor
microenvironments are often slightly hypoxic.
Paclitaxel is a lipophilic small-molecule drug highly successful
in the treatment of breast, ovarian, and lung cancers. Paclitaxel
loading, cell culture release, and biocompatibility studies have
been investigated with a series of PEO-poly(δ-valerolactone) (PVL)
micelles by Allen and coworkers [53]. δ-Valerolactone is identical to
ε-caprolactone except that the lactone ring contains only five carbons
instead of six in ε-caprolactone; thus it is slightly less lipophilic. This
slight reduction in lipophilicity may account for the higher CMC's
10
-5
-10
-6
M over a range of PVL block lengths (0.5-5 kDa) at two
diff erent PEO block lengths (2 and 5 kDa). The reason the reduction
in lipophilicity may increase the CMC is because the micellization
is based on the net diff erence in thermodynamic affinity between
the water and PEO, and the diff erence of PVL and other PVL chains.
The greater the affinity of the core chains for themselves induces a
lower CMC. The PEO-PVL copolymer with both blocks being 2 kDa in
molecular weight was found to retain the highest paclitaxel loaded
concentration (9 mg/mL) following centrifugation and sterile
filtration. This result was expected because all loaded micelles
except this polymer had diameters on the order of magnitude of
the filter. Thus filtration could have physically disrupted the micelle
structure. These copolymers were shown to be biocompatible
with a CHO-K1 cell line up to concentrations of 1 g/L. This micelle
formulation increased paclitaxel aqueous solubility 9000-fold, and
was found to biologically active upon release in MCF-7 breast and
A2780 ovarian cancer cell lines. Although the loading potential of this
class of micelles would only require 28 mL of a 10 wt% copolymer
solution for ovarian cancer and Kaposi's sarcoma treatment, lesser
administered volumes would be desired.
In order to potentially increase paclitaxel loading and decrease
this administered volume, PEO-PCL polymers have been synthesized
with a terminal maleic cap on the PCL end to crosslink the core
[54]. This maleic-capped diblock was then activated with thionyl
chloride, and subjected to radical polymerization with a potassium
peroxodisulfate initiator. A series of diblock and triblock copolymers
were synthesized with PEO block lengths of 2 and 5 kDa, and PCL
blocks lengths ranging from 1.2-18 kDa. As the PCL block length
increased, the paclitaxel loading efficiency increased as expected. As
much as 85% of the loaded paclitaxel was encapsulated in a diblock
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