The Potential and Current Progress of Internalizing Molecules in Targeted Drug Delivery - Intracellular Delivery: Fundamentals and Applications - page 100

functionalize at the cell surface once the conjugates are selectively localized on the
target cells or tissues. However, internalization might still be beneficial for some
alpha-emitting radionuclides with a very short range of alpha-particle emission and
lack of penetrability. In this regard, an internalizing ligand therefore might more be
efficient and helpful than non-internalizing ligands. Indeed, a specific internalizing
molecule with high specificity and affinity to a cellular surface receptor is therefore
a major factor in establishing a targeted drug delivery system.
Over the past few decades, a wide variety of internalizing molecules such as
antibodies, proteins, peptides, folate, carbohydrates, aptamers and other small mol-
ecule ligands have been successfully adapted for the targeted delivery of active drug
substances both in vitro as well as in vivo (Russ and Wagner 2007 ; Ciavarella et al.
2010 ; Yan and Levy 2009 ; Higuchi et al. 2010 ). Recent investigations have
described targeted delivery of various therapeutic agents (e.g. anticancer, antifungal,
antiviral agents, antibiotics, protein, peptide, genes, oligonucleotides and small
interfering RNAs) using different strategies. Through precisely engineering the
internalizing molecules with the drug or delivery vehicle, the recognition and inter-
nalization of the therapeutic compounds by the target tissue can be dramatically
improved. In particular, the advent of nanotechnology has greatly accelerated the
development of drug delivery, providing a large variety of nanocarriers for disease
therapy including liposomes, polymers, carbon nanotubes and quantum dots etc.
(Mok and Park 2009 ; Gullotti and Yeo 2009 ; Kim et al. 2009a ; Wiradharma et al.
2009 ; Liu et al. 2007b ; Zrazhevskiy and Gao 2009 ). Meanwhile, powerful multi-
functional nanomedicines that combine several desirable functions such as thera-
peutics, targeting and imaging in one nanoscale carrier, have been developed to
significantly enhance drug efficacy (Torchilin 2006 ; Zrazhevskiy and Gao 2009 ;
Gao et al. 2010 ; Muthu and Wilson 2010 ; Hart 2010 ). In this review, we discuss
recent advances in targeting strategies for tumors and infectious diseases, with a
particular emphasis on cell internalizing molecules as a targeting strategy.

2 Targeting Strategies for Targeted Delivery

The key for targeted therapy is to accurately identify molecular targets that distin-
guish diseased cells from healthy ones. Ideally, a targeted drug delivery should
enable selective accumulation of the drug in the specific target cells with minimal
adverse side-effects. Generally, targeted delivery can be realized through two strate-
gies (Torchilin 2010 ): ( 1) passive targeting and ( 2) active targeting.

2.1 Passive Targeting

In the first strategy, macromolecules and nanocarriers with sizes below 400 nm in
diameter can travel through the bloodstream and accumulate in tumor via passive