Amphiphilic Block Copolymer Based Nanocarriers for Drug and Gene Delivery - Intracellular Delivery: Fundamentals and Applications - page 266

Fig. 10 Schematic illustration of two types of pH-sensitive micelles. ( a ) pH-induced disintegration
of polymeric micelles; ( b ) pH-induced drug cleavage from polymers
The feasibility of thermo-sensitive micelles for targeting of anticancer drugs to
tumors by dual mechanisms, i.e., passive accumulation/aggregation and the
enhanced release of loaded drugs by an hyperthermic condition induced externally
has been shown (Kim and Park 2002 ; Choi et al. 2006 ). One of the most important
parameters for the design of appropriate thermoresponsive delivery systems is opti-
mization of their lower critical solution concentration (LCST) to temperatures that
are only a few degrees above body temperature. Poly(N-isopropylacrylamide)
(PNiPAAm) is well known to exhibit thermo-reversible phase transition at 32°C
(Chung et al. 1998, 1999 ). Incorporation of hydrophilic groups in PNiPAAm raised
its LCST. The enhancement is more pronounced when the hydrophilic groups (e.g.
amino or hydroxyl group) are at the end of the chain due to the stronger hydrogen
bonding with water (Chung et al. 1998 ; Takei et al. 1993 ; Yoshida et al. 1994 ).
Accordingly incorporation of hydrophobic groups (e.g. alkyl group) shifts the LCST
to lower temperatures and the degree of hydrophobic contribution also depends on
the location of the hydrophobic group (Cammas et al. 1997 ; Kohori et al. 1998 ).
Okano et al. reported on the micellization of PNiPAAm-polystyrene (PNiPAAm-
Pst) and PNiPAAm-poly(d, l-lactide) (PNiPAAm-PDLLA) block copolymers
(Fig. 11 ) (Kohori et al. 1998 ). The synthesized block copolymers exhibited LCSTs
lower than that of pure PNiPAAm at polymer concentration below critical micelle
concentration (CMC), but had an LCST of 32°C when their concentration was
above the CMC as the outer hydrated PNiPAAm shell of micelles behaved like free
PNiPAAm (Nakayama and Okano 2005 ). Above the LCST, the PNiPAAm outer
shell collapses and these micelles aggregate by hydrophobic surface association.
Thermo-responsive PNiPAAm-co-dimethylacrylamide-PDLLA (P(NiPAAm-
co-DMAAm)-PDLLA) micelles showing phase transition at 40°C in phosphate