Biomedical Engineering Reference
In-Depth Information
is a growing list of such molecules that are in essence potential drugs if only a
delivery strategy can be devised to get them to their molecular target in the human
body. Delivery strategies aimed at mediating the selective accumulation of a bio-
logically active molecule fall into two broad classes. The first involves direct
chemical modification of the molecule and includes the traditional approaches of
designing chemical analogs of the molecule as well as more recent approaches of
conjugation to macromolecules or ligands capable of directing site-specific bind-
ing of the bioactive molecule. The second approach is the use of pharmaceutical
carriers in particular those approaches that involve physical entrapment of the
bioactive in the carrier thus offering what might be viewed as a non-chemical
approach to modify the disposition of drug molecules. All chemistry can be per-
formed on the components of the nanocarrier system that can then be loaded with
the drug to afford targeted delivery.
Generally speaking, the role of nanocarriers in drug targeting to tissues is well
accepted. For example, nanocarriers are able to improve the tumor specific accu-
mulation of anticancer drugs by virtue of the Enhanced Permeability and Retention
(EPR) effect (Maeda et al. 2000 ; Greish 2010 ; Fang et al. 2003 ). Such targeting
approaches have been applied to anticancer drugs like doxorubicin (Working et al.
1999 ; Northfelt et al. 1996 ; Gabizon et al. 1989a, b ), daunorubicin (Gill et al. 1996 ;
Cervetti et al. 2003 ), paclitaxel (Yang et al. 2007 ; Sharma et al. 1996, 1997 ), and
cisplatin (Stathopoulos 2010 ) with commercial success in some cases (eg Doxil,
Daunosome). Current approaches also routinely focus on improving cell specific
accumulation of the nanocarriers as well. However, nanocarrier targeting at a sub-
cellular level has until recently not been as widely pursued perhaps due to techno-
logical limitations or the argument that once a drug gets inside a cell it will
eventually find its way to the subcellular target. There often seems to be an assump-
tion that mediating cell cytosolic internalization is adequate to ensure the interac-
tion of the drug molecule with its final sub-cellular target by virtue of simple
diffusion of the drug molecule and random interaction with various sub-cellular
structures in the cell. However, it has become increasingly evident during the last
decade that such an assumption cannot always be made (Duvvuri and Krise 2005 ;
Breunig et al. 2008 ; Torchilin 2006 ; Li and Huang 2008 ; Kaufmann and Krise
2007 ; Panyam and Labhasetwar 2003 ; Weissig 2003, 2005 ; Weissig et al. 2004,
2007 ). The potential role that nanocarriers play in controlling the subcellular dispo-
sition of bioactives is, therefore, certainly worth examining.
2
Potential Roles of the Nanocarrier in Controlling
Sub-cellular Disposition of Bioactives
Bioactive molecules can potentially act in various sub cellular locations that can be
roughly divided into general cytosolic locations, the surface of organelles and spe-
cific regions inside organelles. The nature of the molecule and its potential sites of
action together influence the design of the nanocarrier delivery strategy. Cytosolic
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