The Potential and Current Progress of Internalizing Molecules in Targeted Drug Delivery - Intracellular Delivery: Fundamentals and Applications - page 101

leakage, thereby increasing the concentration of drugs in tumors and enhancing the
therapeutic index (Yuan et al. 1995 ; Moghimi et al. 2001 ). This passive mechanism
is called the enhanced permeability and retention (EPR) effect (Matsumura and
Maeda 1986 ; Greish 2007 ). Since passive targeting relies on a size-flow-organ/tissue
filtration that is generally limited to tumors and lymph nodes (LNs), drug particles/
carriers can theoretically be designed and engineered with appropriate sizes
(e.g. 100-400 nm) and surfaces (e.g. PEGylated surface) (Maeda 2010 ). Currently,
many studies have taken advantage of the EPR effect to achieve passive targeting
of drug nanocarriers to most human tumors. And some of them have been approved
for clinical use such as Doxil (Doxorubicin encapsulated by PEGylated liposome)
(Gabizon 2001 ). In the treatment of HIV, LNs are important sites for targeting
HIV-1 replication and they have been exploited as a promising passive targeting site
(Gupta and Jain 2010 ; Gunaseelan et al. 2010 ).

2.2 Active Targeting

In the second strategy, an actively recognized moiety specific to the target sites
of interest is an essential component. These actively recognized molecules can
be precisely decorated on the therapeutic agents or their delivery vehicles, func-
tioning as cell or tissue-specific homing agents (Peer et al. 2007 ; Gullotti and
Yeo 2009 ). Typically, by utilizing biologically specific interactions such as
antigen-antibody binding or ligand-receptor interactions, these targeting mole-
cules facilitate the cellular uptake of therapeutic agents via receptor-mediated
endocytosis or cellular membrane permeation, thereby increasing the local con-
centration of the drug in the targeted cells or tissues, thereby improving the
therapeutic efficacy at lower doses.

2.3 Combinatorial Targeting

Despite numerous successful examples using either one of the above strategies, a
combination of passive and active targeting also has been exploited to provide the
most efficient targeted delivery system (Torchilin 2010 ). In this regard, a combina-
torial targeting results in twice the enrichment at the cellular and tissue/organ levels
(Akbulut et al. 2009 ). For example, for a targeted nanocarrier system, an appropri-
ate nano-scale size can allow preferential accumulation in the tumor tissue/organ in
the passive mode. Once the nanocarrier is concentrated at the tumor site, a cell type-
specific affinity internalizing molecule such as an antibody, peptide, folate or
aptamer engineered on the nanocarrier surface would further facilitate selective
internalization into the targeted tumor cells. In comparison with traditional small
molecule drugs or non-targeted nanocarriers, targeted nanocarriers that combine
the above two desirable properties could not only prolong circulation time and