Amphiphilic Block Copolymer Based Nanocarriers for Drug and Gene Delivery - Intracellular Delivery: Fundamentals and Applications - page 260

Table 1 Polymeric micellar delivery systems in clinical trials

Polymer
category

Progress
phase Trade name Incorporated drug References

NK911 PEO-PLAA DOX/chemically

conjugated
and physically
loaded

II (Matsumura

2008 ;
Matsumura
et al. 2004 )

NK105 PEO-PLAA Paclitaxel/physically

loaded

II (Hamaguchi et al.

2005a )

NC-6004 PEO-PLAA Cisplatine/to form

complex

I/II a (Uchino et al.

2005b )

SP1049C Pluronic DOX/physically

loaded

III a (Sharma et al.

2008 )

PAXCEED ® PEO-poly(ester) Paclitaxel/physically

loaded

I/II a (Zhang et al.

2005a )

Genexol ® -PM PEO-poly(ester) Paclitaxel/physically

loaded

II/III/IV a (Kim et al. 2007 ;

Lee et al. 2008 )

NK012 PEO-p(Glu) 7-Ethyl-10-hydroxy

camptothecin/
chemically
conjugated

I/II a (Koizumi et al.

2006 )

a Updated from http://clinicaltrials.gov as of August 2010

bonds (Fig. 7 ). Ringsdorf et al. reported on the preparation of micelle-forming conjugates
of cyclophosphamide (CP) sulfide and PEO-poly(L-lysine) (PEO-poly(L-Lys))
(Yokoyama et al. 1991 ; Kataoka et al. 1993 ). Simultaneous conjugation of fatty acids
to the polymeric back bone was used to increase the thermodynamic stability of this
system. This formulation was found efficient in the stabilization of active CP metabo-
lite, in vivo , and caused a fivefold increase in the life span of L1210 tumor bearing
mice even at a reduced CP-equivalent dose. Block copolymer drug conjugates of
PEO-P(L-Asp-DOX) have been developed by Kataoka's group (Bae et al. 2003a ).
DOX was covalently conjugated to the side chain of the P(L-Asp) segment by an
amide bond between the carboxylic group in P(L-Asp) and the primary amine group
of DOX. However, the amide bound was too stable and did not provide efficient drug
release. In further studies, DOX was conjugated to the P(L-Asp) through a hydrazone
linker that is stable under physiological pH, but cleavable under acidic pH of endo-
somes/lysosomes (Bae et al. 2005b ). The PEO-p(Asp-Hyd-DOX) showed increased
maximum tolerable dose, and increased blood and tumor DOX levels in C 26 tumor
bearing mice (Nishiyama et al. 1999, 2003 ). In addition, the pH sensitive micellar
DOX conjugate showed better therapeutic efficacy than free drug at corresponding
maximum tolerable doses.
Incorporation of cisplatin (CDDP) into the PEO-P(L-Asp) and PEO-P(L-
Glutamine) (PEO-P(L-Glu)) micelles to form polymer-drug complex has been
achieved (Fig. 8 ) (Uchino et al. 2005a ). Release of CDDP from the complexes is
triggered in the presence of high concentrations of salt in medium, which will
replace the complexed drug. The PEO-P(L-Glu) formulation of CDDP is currently
in clinical trials in Japan under the name of NC-6004 (Table 1 ) (Ward et al. 2002 ;
Lee et al. 2005b ; Katayose and Kataoka 1997, 1998 ).