The Potential and Current Progress of Internalizing Molecules in Targeted Drug Delivery - Intracellular Delivery: Fundamentals and Applications - page 110

cells (Ferkol et al. 1996 ). The mannose-coating nanoparticles have been widely
used for targeted delivery of anti-HIV drugs. For example, Jain et al. have used
mannose-conjugated, fifth generation poly(propyleneimine) (MPPI) dendrimers to
deliver lamuivudine (3TC) to HIV-1 infected MT-2 cells. Significant increases in
the cellular uptake of 3TC were observed compared with free drug and non-targeted
PPI dendrimers (Dutta and Jain 2007 ). In another study, MPPI nanocarriers also
delivered efavirenz (EFV) to human monocytes/macrophages. Similarly, stavudine
(d4T, brand name Zerit) also has been loaded in mannosylated liposomes and has
been evaluated in vitro for anti-HIV activity (Dutta et al. 2007 ).

3.6 Aptamer-Mediated Drug Delivery

Aptamers are evolved, single-stranded nucleic acids that can specifically recognize
and bind their cognate targets by means of well-defined stable, three-dimensional
structures (Mayer 2009 ; Famulok et al. 2007 ). Over the past 20 years, numerous
nucleic-acid aptamers have been raised against a wide variety of targets (Nimjee
et al. 2005 ). Moreover, their many favorable characteristics, such as the low nano-
molar dissociation constants and exquisite specificity, small size, stability, lack of
immunogenicity, and the ability to be chemically synthesized with various base
and backbone modifications make them versatile tools for diagnostics, in vivo
imaging, and targeted therapeutics. Currently, the advances in the development of
DNA or RNA aptamers specifically targeting membrane receptors to deliver and
enhance the efficacy of other therapeutics agents have drawn attention for exploiting
specific cell-internalizing aptamers as targeted drug delivery carriers (Zhou and
Rossi 2009 ; Yan and Levy 2009 ). An increasing number of cell-type specific
RNA and DNA aptamers targeting PSMA (prostate-specific membrane antigen)
(Lupold et al. 2002 ); HIV-1 gp120 (Cohen et al. 2008 ; Dey et al. 2005 ); CD4
(cluster of differentiation 4) (Kraus et al. 1998 ); TN-C (tenasin-C) (Hicke et al.
2001 ), EGFR (epidermal growth factor receptor) (Li et al. 2010 ), PTK7 (protein
tyrosine kinase 7) (Xiao et al. 2008 ), TfR (transferrin receptor) (Chen et al. 2008 ),
NCL (nucleolin) (Shieh et al. 2010 ) and MUC1 (mucin protein) (Ferreira et al.
2009 ), have been adopted for targeted delivery of the various molecules of inter-
est. Four representative examples are discussed below.

3.6.1 Anti-PSMA RNA Aptamer

PSMA, a trans-membrane protein, is highly expressed in human prostate cancer
and the vascular endothelium. It has been known that PSMA can be constitutively
endocytosed into PSMA-positive LNCap cells and be continually recycled from the
plasma membrane, thereby allowing for intracellular drug transport (Tasch et al.
2001 ; Liu et al. 1998 ). Since several 2¢-Fluoro modified anti-PSMA RNA aptamers
with nanomolar binding affinity were isolated by Lupold et al. (Lupold et al. 2002 ),