1
22
european journal of pharmaceutical sciences 2 7 ( 2 0 0 6 ) 115–122
drug release rate. In Fig. 7, the photographs of the cells treated
Chung, J.E., Yokoyama, M., Okano, T., 2000. Inner core segment
design for delivery control of thermo-responsive polymeric
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Chung, J.E., Yokoyama, M., Yamato, M., Aoyagi, T., Sakurai, Y.,
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with either free DOX (Fig. 7(a and b)) or DOX loaded MBC1
◦
(
Fig. 7(c and d)) for 3 days at 37 and 42 C are shown together
with control (Fig. 7(e and f)) at each temperature. Most cells
exposed to free DOX (1 g/mL) were killed due to DOX cyto-
toxicity at both temperatures. However, the cells with same
amount of DOX in MBC1 NP were observed with different
◦
shapes between two temperatures. The NP at 37 C (Fig. 7(c))
Huh, K.M., Bae, Y.H., 1999. Synthesis and characterization of
poly(ethylene glycol)/poly(l-lactic acid) alternating
multiblock copolymers. Polymer 40, 6147–6155.
◦
demonstrated low cytotoxicity against LLC cells, while at 42 C
it killed the cell almost completely like a free DOX (Fig. 7(d)).
The MTT assay was carried out for quantitative analysis in
the cytotoxicity of the NP. In case of free DOX, there was no
noticeable difference in the cytotoxicity between two temper-
atures at the DOX concentration range of 1 ng/mL to 10 g/mL
Kikuchi, A., Okano, T., 2002. Intelligent thermoresponsive
polymeric stationary phases for aqueous chromatography of
biological compounds. Prog. Polym. Sci. 27, 1165–1193.
Lee, E.S., Na, K., Bae, Y.H., 2005a. Super pH-sensitive
multifunctional polymeric micelle. Nanoletters 5, 325–329.
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◦
(
Fig. 8(a)). However, DOX loaded MBC1 at 42 C (50% inhibitory
concentration (IC50); about 0.5 g/mL) showed approximately
◦ ◦
0 times higher cytotoxicity than that at 37 C. IC50 at 37 C
2
Lee, E.S., Shin, H.J., Na, K., Bae, Y.H., 2003. Poly(l-histidine)/PEG
block copolymer micelle and pH-induced destabilization. J.
Control. Rel. 90, 363–374.
was estimated to be higher than 10 g/mL from Fig. 8(b). It is
interesting to note that the temperature effect on the cytotox-
icity is far more than expected because the released amount
Lee, K.Y., Jo, W.H., Kwon, I.C., Kim, Y.H., Jeong, S.Y., 1998.
Structural determination and interior polarity of
self-aggregates prepared from deoxycholic acid-modified
chitosan in water. Macromolecules 31, 378–383.
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◦
of DOX at 42 C for 24 h was less than twice of the amount
◦
at 37 C. One possible explanation for this observation is that
the more hydrophobic surface of the NP induced by temper-
ature may facilitate internalization of the NP in the cells as
noticed with pH-sensitive micelles (Na et al., 2003b) and other
temperature-sensitive micelles (Chung et al., 1999, 2000). The
details of temperature-induced internalization of MBC NP will
be a further subject of investigation.
4
.
Conclusion
The nanoparticles prepared from poly(ethylene glycol)/poly(l-
lactic acid) alternating multi-block copolymer were investi-
gated as an anti-cancer drug carrier which responded to
local temperatures. The sensitivity in the MBC nanoparticles
depended on PLLA length in the polymers. The temperature-
acetate/oligo(methacryloyl sulfadimethoxine) (PA/OSDM)
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2003a. Self-assembled nanoparticles of
hydrophobically-modified polysaccharide bearing vitamin H
as a targeted anti-cancer drug delivery system. Eur. J.
Pharm. Sci. 18, 165–173.
induced interior structural changes of the nanoparticles at
◦
4
2 C led to accelerated DOX release. The MBC nanoparticle
showed enhanced cytotoxicity against LLC cells. The result
indicated that the thermo-sensitivity of MBC may show the
synergistic effect with local hypothermia for the treatment of
tumor.
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