Biomedical Engineering Reference
In-Depth Information
(B)
(a)
(A)
1
10
100
1000
10000
Diameter (nm)
(b)
1
10
100
1000
10000
Diameter (nm)
FIGURE 6.1
(A) Biotin-conjugated copolymeric nanoparticles composed of PEG and PCL copolymers
observed by fi eld emission scanning electron microscopy. (B) Typical size distribution of biotin-conjugated
PEG/PCL block copolymeric nanoparticles determined using a light scattering method after drug loading:
(a) biotin-conjugated PEG/PCL nanoparticles, and (b) PEG/PCL nanoparticles without biotin group. (From
Kim, S.Y., Cho, S.H., Chu, L.Y., and Lee, Y.M., Macromolecular Research, in press
.
)
between the core-forming block and the incorporated drug. The micelle corona should provide
effective steric protection for the micelle [38]. The molecular weight, polydispersity, charge, and
hydrophilic-hydrophobic character of the block polymers infl uence biodistribution, clearance,
biological activity, toxicity, and drug-loading effi ciency [5].
Such nanoparticle drug carriers are designed by grafting PEG or polysaccharide chains using
the concept of physicochemical steric repulsion to avoid protein adsorption [12]. This approach
allows drug carriers to be maintained in the blood circulation for longer periods of time, and the
resulting extravasation to the non-RES located cancers may become possible.
PEG-
block
-poly(aspartic acid) (PEG-
b
-P[ASP]) copolymers chemically conjugated with doxo-
rubicin spontaneously form polymeric micelle, which can effi ciently entrap free Dox in the inner
core, and the optimized formulation called NK911 is now being studied in a phase II clinical trial at
the National Cancer Center (NCC) Hospital in Japan [27]. In this formulation, doxorubicin chemi-
cally conjugated to the polymer side chain is pharmacologically inactive but contributes to the
stable physical entrapment of free doxorubicin into the micellar core through
π
-
π
interaction of the
anthracycline structure in doxorubicin between the conjugated and unconjugated ones, also allow-
ing its sustained release from the micellar core [27].
The micelles presented by Maysinger et al. likely enter the cell by endocytosis, perhaps after
their nonspecifi c association with the cell surface. The micelle-incorporated small hydrophobic
drug can then enter the cytoplasm at a much higher rate by diffusing across the endosomal mem-
brane. In addition, the surfactant nature of the micelle-forming block copolymers may also enhance
the permeability of the endosomal membrane or even disrupt it. The detection of micelles in the
cytoplasm suggests that the latter mechanism is at least partially responsible [29,51]. Kabanov et al.
have demonstrated that Pluronic block copolymers based on PEG-poly(propylene glycol)-PEG can
interfere directly with the function of Pgp [29,52].
