Amphiphilic Block Copolymer Based Nanocarriers for Drug and Gene Delivery - Intracellular Delivery: Fundamentals and Applications - page 268

role in biorecognition (Yasugi et al. 1999 ; Nagasaki et al. 1998 ). The interaction of
the sugar installed PEO─PDLLA micelles with lectin was investigated to simulate
binding to glyco-receptors. Binding to Con A was investigated for mannose-micelles
and interaction with Ricinus communis agglutinin (RCA-1) was assessed for galac-
tose and lactose (Nagasaki et al. 2001 ). In general, lactose-micelles exhibited rapid
binding to the protein bed. An increase in the ligand density resulted in multivalent
binding and diminished dissociation kinetics. Development of galactose-modified
PEO-poly(g-benzyl-L-glutamate) (galactose-PEO-(PEO-PBLG) micelles and their
application for PXT in ASGP expressing HepG2 cells have been reported (Cho et al.
2001 ). Kataoka et al. also reported on the development of lactose conjugated
PEO-poly(2-(dimethylamino)ethyl methacrylate) (PEO-PAMA) that can form PIC
micelles with plasmid DNA (pDNA) and efficiently transfect HepG2 cells
(Wakebayashi et al. 2004b ).
Folic acid - Folic acid (folate) has become an attractive ligand for targeting can-
cer cells because its receptor is overexpressed in many human cancers. It is an
essential vitamin for the biosynthesis of nucleotide bases and is consumed in
elevated quantities by proliferating cells. Folate has been covalently attached to
liposomes, polymer conjugates and nanoparticles (Hilgenbrink and Low 2005 ;
Reddy et al. 2005 ). The poor water-soluble drug PXT was physically loaded into
the folate-modified PEO-PCL micelles (Park et al. 2005 ). Folate-PEO-PCL
micelles exhibited significantly higher cytotoxicity compared to unmodified
micelles against human breast adenocarcinoma (MCF-7), human uterine cervix
adenocarcinoma (HeLa 229) cells, whereas conjugation of folate on the micellar
carrier had no significant effect on the cytotoxicity of PEO-PCL micellar PXT in
normal human fibroblasts (HF). Park et al. developed a mixed polymeric micellar
system composed of folate-PEO-poly(D, L-lactic-co-glycolic acid) (folate-
PEO-PLGA) and PEO-PLGA-DOX conjugates (Yoo and Park 2004 ). The mixed
micelles exhibited higher cytotoxicity than DOX, suggesting an increased intrac-
ellular transportation of DOX to cells through folate receptor medicated endocy-
tosis. Systemic administration of this formulation significantly retarded tumor
growth compared to unmodified micelles. Biodistribution studies also indicated
an increased accumulation of DOX in tumor tissue. Conjugation of folic acid to
PEO-P(L-Lys) has been pursued to target therapeutic proteins or other negatively
charged bioactive macromolecules (Hwa Kim et al. 2005 ).
RGD peptides - Peptides containing the RGD sequence can recognize integrins
overexpressed on the endothelial cells of the tumor neovasculature or metastatic
tumor cells. Gao et al. developed cyclic (Arg-Gly-Asp-d-Phe-Lys) (cRGDfK)
modified PEO-PCL micelles that can selectively deliver drugs to angiogenic tumor
endothelial cells (Fig. 12a ) (Nasongkla et al. 2004 ). Confocal laser scanning
microscopy exhibited 30 times higher accumulation of DOX-loaded in cRGDfK-
modified micelles compared to unmodified micelles in human Kaposis sarcoma
tumor endothelial SLK cells.
Our group has developed RGD modified PEO-PCL micelles containing physi-
cally or chemically incorporated DOX (Fig. 12b ) (Xiong et al. 2007a ). Higher uptake