Approaches to Achieving Sub-cellular Targeting of Bioactives Using Pharmaceutical Nanocarriers - Intracellular Delivery: Fundamentals and Applications - page 63

machinery, other properties of organellar compartments like membrane lipid
composition (Fernandez-Carneado et al. 2005 ), membrane potential (D'Souza et al.
2008 ) and even intra-organellar pH (Torchilin et al. 2009 ) have been explored for
achieving selective delivery to organelles.

3 Prevalent Nanocarrier Design Approaches

It currently appears that nanocarrier design for subcellular targeting is based on the
fractal symmetry between the case of drug delivery to a cell and drug delivery to a
molecular target inside a sub-cellular compartment. The cell could be viewed as
being a small, slightly simpler but nonetheless highly organized “body” with
“organs” (organelles) and “cells” (defined structures and molecular arrangements)
within these organs. Therefore principles that have been explored for organ and cell
specific targeting are being applied at the subcellular level. Nanocarriers are either
being modified with sub cellular targeting ligands or are being prepared from mate-
rials that have inherent subcellular accumulation characteristics. As alluded to in
the previous section, much of this line of thinking is based on current understanding
of viral particles. Viruses could be considered naturally occurring nanocarriers with
the ability to selectively deliver their DNA cargo to a sub-cellular target (the
nucleus). It is perhaps safe to say that much of what we know about the cellular
interaction and sub-cellular disposition of nanocarriers has some how been associ-
ated with investigations into mimicking the DNA delivery capability of viruses
using artificial nanocarriers.

3.1 Nanocarriers Modified with Sub-cellular Targeting Ligands

Most nanocarriers are believed to enter the cell by endocytic mechanisms and could
therefore be considered as having a predisposition for accumulation in endosomes
and potentially lysosomes as well. This predisposition of particulate systems is
particularly useful as pathological conditions associated with endosomes and lyso-
somes could potentially benefit from therapies targeting these pathways (Bareford
and Swaan 2007 ; Gregoriadis and Ryman 1971 ; Castino et al. 2003 ; Tate and
Mathews 2006 ). The fate of the nanocarrier is dependent on the mechanism of
vesicular internalization (Bareford and Swaan 2007 ). For example, nanoscale drug
carrier systems taken up by clathrin-dependent receptor-mediated endocytosis
(RME) are most likely to undergo lysosomal degradation, while clathrin-indepen-
dent RME may lead to endosomal accumulation (Bareford and Swaan 2007 ).
Consequently, the type of targeting moiety displayed by the nanocarrier system
determines whether the carrier delivers its cargo to either endosomes or lysosomes.
Several endocytic targeting moieties have been studied and include folic acid, low-
density lipoprotein, cholera toxin B, mannose-6-phosphate, transferrin, riboflavin,