The Potential and Current Progress of Internalizing Molecules in Targeted Drug Delivery - Intracellular Delivery: Fundamentals and Applications - page 113

was used to disrupt the aptamer's active structure, the cellular uptake of the
aptamer-liposome was inhibited, thereby suggesting a novel controllable targeted
drug delivery system. Most recently, Shieh et al. physically conjugated AS1411
with six molecules of a porphyrin derivative (TMPyP4), a broadly used photody-
namic therapeutic agent (Shieh et al. 2010 ). By NCL-mediated internalization, the
aptamer-TMP complex exhibited a higher TMPyP4 accumulation and specific
photo-damage in MCF7 breast cancer cells.

3.7 Other Internalizing Molecule-Mediated Drug Delivery

In addition to the afore-mentioned more popular internalizing molecules, other
specific ligands have been applied for targeted drug delivery.
Anisamide has served as a targeting ligand for tumor cells expressing the sigma
receptor, a transmembrane protein that plays a role in regulating ion channels.
It was found that sigma receptors are over-expressed in a diverse set of human and
rodent tumor cell lines (Vilner et al. 1995 ). Small molecules such as asanisamide,
haloperidol and opipramol have been reported as sigma receptor ligands and have
been developed as radio-imaging agents for tumors (Maurice and Su 2009 ; Cobos
et al. 2008 ; John et al. 1999 ). These receptor-specific ligands can be linked to vari-
ous nanocarriers, or be directly conjugated to the oligonucleotide itself. For
example, Huang and colleagues have successfully conjugated the high-affinity
sigma receptor ligand asanisamide to lipopolyplex nanocarriers for specifically
delivering doxorubicin or siRNAs to tumors in animals (Li and Huang 2006 ;
Banerjee et al. 2004 ). Their subsequent studies confirmed that the cellular uptake
was mediated via a sigma receptor dependent pathway. Similarly, haloperidol-
modified lipoplexes were shown to mediate tenfold greater delivery of DNA to
breast carcinoma cells compared with the control lipoplexes (Mukherjee et al.
2005 ). Most recently, anisamine also was directly conjugated to antisense oligo-
nucleotides (ONs) (Nakagawa et al. 2010 ). The trivalent anisamide-ONs conjugate
significantly enhanced receptor-specific cell uptake and biological activity.
Hyaluronan, also known as hyaluronic acid (HA) or sodium hyaluronate, is a
natural anionic polysaccharide which can be efficiently taken up into cells by HA
receptor mediated endocytosis (Stern et al. 2006 ; Prevo et al. 2001 ). Therefore,
HA and its derivatives have been widely used as novel targeting ligands as well as
target specific, long acting drug carriers of various therapeutic agents, including
Dox, paclitaxel, proteins, peptides and nucleotide therapeutics (Oh et al. 2010 ). For
example, the HA-modified long-circulating liposomes actively targeted tumors
over-expressing the HA receptor (Peer and Margalit 2004a, b ). The HA-poly-L-
lysine (PLL) conjugate was shown to target sinusoidal epithelial cells in the liver
(Jiang et al. 2009 ). The delivery of siRNA with HA modified PEI significantly
improved gene silencing in HA receptor over-expressing cells. Most recently, HA
derivative-quantum dot (HA-QD) conjugates facilitated targeted delivery and
accumulated more efficiently in the cirrhotic liver than the normal liver after
tail-vein injection (Kim et al. 2010 ).