Amphiphilic Block Copolymer Based Nanocarriers for Drug and Gene Delivery - Intracellular Delivery: Fundamentals and Applications - page 258

complex micelles (PIC)s. In micelle-forming polymer-drug conjugates, drug is
incorporated and stabilized within the carrier through formation of chemical bonds
between the functional group(s) of the polymeric backbone and the drug (Aliabadi
and Lavasanifar 2006 ). When solubilization of drugs in the polymeric micelles is
achieved via hydrophobic interactions or hydrogen bonds between the core-forming
block and drug, the resulting system is called polymeric micellar nano-containers.
Polymeric micellar nano-containers may be prepared by the direct addition and
incubation of drug with block copolymers in an aqueous environment, only if the
block copolymer and the drug are water soluble. The method, however, is not very
efficient in terms of drug-loading levels and not feasible for most block copolymer/
drug structures. Instead, physical incorporation of drugs into polymeric micellar
nano-containers is usually accomplished through dialysis, oil/water emulsion, solvent
evaporation, co-solvent evaporation, or freeze drying method (Aliabadi and
Lavasanifar 2006 ). Finally, in (PIC)s, drug incorporation is promoted through elec-
trostatic interactions between oppositely charged polymer/drug combinations.
Neutralization of the charge on the core-forming block will trigger self assembly of
the PIC and further stabilization of the complex within the hydrophobic environment
of the micellar core (Aliabadi and Lavasanifar 2006 ). PICs have been investigated
for the delivery of different therapeutic moieties that carry charge (drugs (Nishiyama
et al. 1999, 2003 ), peptides (Yuan et al. 2005 ) and DNA (Yuan et al. 2005 ;
Wakebayashi et al. 2004a, b ; Itaka et al. 2003 )). Drug release from polymeric
micellar drug conjugates, nano-containers and PIC micelles is governed by different
mechanisms (Fig. 3 ).
To date, seven polymeric micellar formulations have reached preclinical and
clinical trials (Table 1 ) (Aliabadi and Lavasanifar 2006 ; Mahmud et al. 2007 ;
Sutton et al. 2007 ; Matsumura 2008 ).
A micellar nano-container of doxorubicin (DOX) composed of PEO-poly
(L-aspartate) with conjugated DOX (PEO-P(Asp-DOX)) containing physically
encapsulated DOX, namely NK911 (Fig. 4 ), is one of the few polymeric micellar
formulations with a favorable pharmacokinetics for passive drug targeting
(Danson et al. 2004 ). A PEO-poly(propylene oxide)-PEO (PEO-PPO-PEO),
i.e., Pluronic ® micellar DOX, namely SP1049C, has shown good encapsulation,
but similar pharmacokinetic profile to that free DOX in human (Hamaguchi et al.
2005b ; Kim et al. 2004 ).
Development of polymeric micellar nano-containers for the delivery of pacli-
taxel (PXT) has also been pursued. Both PEO-poly(D-lactide) (PEO-PDLA)
and PEO-p(L-Asp) micellar formulations of PXT were successful in increasing
the water solubility of PXT (Hamaguchi et al. 2005b ). However, except for the
NK105 (the PEO-poly(4-phenyl-1-butanoate) (L-aspartamide) formulation)
(Fig. 5 ), other polymeric micelles failed to show any benefit over PXT commer-
cial formulation, Taxol ® , in passive PTX targeting (Zhang et al. 2005b ).
Conjugation of drugs to PEO-poly(ester)s has been accomplished by func-
tionlization of the poly(ester) end, followed by reaction with drugs (Fig. 6 ) (Yoo
and Park 2001 ; Hirano et al. 1979 ). In this approach, only one drug molecule is
introduced for each copolymer molecule. In our group, DOX was conjugated to
the PEO-poly(e-caprolactone) (PEO-PCL) backbone by the reaction between