Biomedical Engineering Reference
In-Depth Information
acid-triggered drug release to effectively deliver intact DOX to sensitive cancer
cells and derivatized DOX to resistant cancer cells (Xiong et al.
2010a
). Briefly,
DOX was chemically conjugated to the micellar core by amide or hydrazone link-
ages, while the RGD4C moieties specifically homing to integrin anb3 receptors
expressed by cancer cells (e.g. MDA435/LCC6 sensitive and resistant cells) were
used to functionalize the micellar shell (Fig.
13a, b
). These targeted micelles
showed markedly increased cellular uptake mediated by RGD4C modification.
In particular, pH-triggered drug release of intact DOX and derivatized DOX from
hydrazone and amide bound DOX-conjugates, respectively led to changed cellular
distribution and cytotoxicity of the carried DOX against both cell lines. As
expected, subcellular distribution revealed that targeted micelles containing hydra-
zone-linked DOX showed preferential accumulation in nucleus in sensitive cells,
while micelles containing amide-linked DOX showed preferential DOX accumu-
lation in mitochondria in resistant cells after 24 h of incubation (Fig.
13c
). SCID
mice bearing with human sensitive and resistant tumors have been optimally
treated by the RGD4C-functionalized micelles with hydrazone-linked and amide-
linked DOX, respectively. The results point to the potential of these multifunc-
tional polymeric micelles as the custom-designed carrier for personalized cancer
chemotherapy.
Including a combination of an ultra pH-sensitive polymer and cell penetrating
TAT protein in the structure of polymeric micelles by Bae et al. led to the preparation
of another multifunctional polymeric micellar system (Sethuraman and Bae
2007
).
The delivery system consisted of TAT-attached PEO-poly(L-lactic acid) (PEO-
PLLA) micelles and the TAT shield, i.e. an ultra pH-sensitive PEO-poly(methacryloyl
sulfadimethoxine) (PEO-PSD). At pH 7.4, the anionic PSD is complexed with
cationic TAT of the micelles via electrostatic interaction so that the non-specific cell
penetrating TAT peptides on micelles are shielded by PEO-PSD. The PSD will
become neutral below pH 7.0. Therefore, deshielding of TAT micelle is triggered
by the lower pH of the tumor milieu, exposing TAT to the cells.
Multifunctional mixed micelles of folate-PEO-poly(L-Histidine) (folate-PEO-
P(L-His)) and PEO─PLLA were developed also by the latter group (Lee et al.
2003a
). The mixed micelles were able to recognize the minute differences in pH
and provide enhanced release below pH 7.4. The superior cytotoxicity of this sys-
tem at tumor pH (6.8-7.2) compared to physiological pH (7.4) was demonstrated
in MCF-7 cells. The combined mechanisms of pH-triggered release and active
internalization by folate receptor improved the
in vitro
cytotoxicity of encapsulated
DOX surpassing that of free drug in sensitive MCF-7 cells (Lee et al.
2003a
). This
system was effective in sensitizing MCF-7 resistant cells to DOX achieving similar
IC
50
to that of free DOX in sensitive cell line. The multifunctional polymeric micel-
lar carrier has shown superior
in vivo
efficacy to that of free DOX or DOX encap-
sulated in pH sensitive micelles without folate (Lee et al.
2005a
).
The same research group has reported on the formation of multifunctional mixed
micelles of PEO-P(L-His) and PLLA-PEO-P(L-His)-biotin (Lee et al.
2005c
). In
this system, biotin on the micellar surface was used to enhance tumor specificity.
P(L-His) section was used as a pH sensitive segment that can hypothetically cover
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