The Potential and Current Progress of Internalizing Molecules in Targeted Drug Delivery - Intracellular Delivery: Fundamentals and Applications - page 109

Folate has been successfully decorated on polymer, nucleic acids, liposomes,
dendrimers, quantum dots and polymeric micelles. For example, a folate-PEG-PEI
nanoconjugate delivered plasmid DNA or oligonucleotides into tumor cells in a
target specific manner (Cho et al. 2005 ). Polyhydroxyalkanoates (PHAs) were
modified with folate via covalent bonds for targeted Dox delivery (Zhang et al.
2010 ). Similarly, folate-targeted liposomes specifically transported daunorubicin
(Ni et al. 2002 ) and Dox (Goren et al. 2000 ) into various tumor cells and increased
the cytoxic killing of these cells. Folate-linked packaging RNA (pRNA) was shown
useful for selectively delivering siRNAs against coxsackievirus B3 (CVB3) thereby
effectively inhibiting virus replication (Zhang et al. 2009 ). In addition, a folate
analog, methotrexate (MTX), has been conjugated with magnetic nanoparticles for
targeted drug delivery and specific imaging (Duthie 2001 ).

3.5 Carbohydrate-Mediated Drug Delivery

Lectin-carbohydrate interaction is another consideration for active targeting. It is
known that the cell surface is rich in carbohydrate moieties attached to both mem-
brane glycolipids and glycoproteins (Boraston et al. 2004 ; Kannagi et al. 2004 ).
Therefore, the carbohydrate moieties represent a potential recognition ligand for
targeted therapeutic delivery.

3.5.1 Galactose and Lactose

The asialoglycoprotein receptors are expressed on the surface of hepatocytes and
are able to mediate endocytosis and subsequent internalization into hepatoma cells.
The oligosaccharides, such as galactose (a monosaccharide) and lactose (a disac-
charide) have been used as targeting molecules for hepatocyte-specific delivery
through asialoglycoprotein receptor-mediated endocytosis (Cook et al. 2005 ; Lim
et al. 2000 ). For example, a galactosylated liposome was reported to deliver Dox to
the hepatocytes (Wang et al. 2006 ). The attachment of galactose to the cyclodextrin-
containing polymer via a PEG-adamantine linker allowed for targeted nucleic acid
delivery (Bartlett and Davis 2007 ). Oishi et al. also developed a lactosylated PEG-
siRNA conjugate through an acid-labile linkage, which could efficiently release
free siRNA once this conjugate entered acidic endosomal compartment (Oishi et al.
2005 , 2007 ).

3.5.2 Mannose

It has been known that mannose receptors are highly expressed in macrophages,
dendritic cells and other hematopoietic cells important for innate immune
responses. Mannose is recognized by a mannose receptor and is internalized into