Mass Transport via Cellular Barriers and Endocytosis - Intracellular Delivery: Fundamentals and Applications - page 27

4.2 Cellular Zip-Codes

Blobel and Dobberstein hypothesized in 1975 that “zip-codes” were responsible for
targeting proteins toward the endoplasmic reticulum (Blobel and Dobberstein
1975 ). Blobel was awarded the Nobel Prize for Physiology or Medicine in 1999
(Heemels 1999 ), when the signal hypothesis based on “zip-codes” held true for not
only transporting the proteins towards the endoplasmic reticulum but for other
intracellular organelles as well. By maneuvering the “zip-code” of a protein, the
sub-cellular destination of the protein could be changed. Since various diseases
have different subcellular origination, an opportunity is presented to use zipcodes
to drive intracellular trafficking in a disease-specific manner. Therefore it is crucial
to analyze and understand the multiple signaling elements and their role in
“zip-code” change to target an individual organelle and the specific disease (Davis
et al. 2007 ). For example, targeting lysosomes has been applied in treatment of
lysosomal storage diseases such as TaySach's disease, Lesh-Nyhan-syndrome and
adenosine deaminase insufficiency. Targeting caveolae has been proposed to influ-
ence cancer, atherosclerosis, Alzheimer's disease, and muscular dystrophy (Prokop
and Davidson 2008 ).
A number of intracellular DNA delivery studies for gene delivery have been
directed towards the nuclear genome, or more recently, to the mitochondria
(Torchilin et al. 2002 ). With mitochondria being a suitable target of proapoptotic
drugs for cancer therapy, and lysosomes being the target for lysosomal storage
diseases, the need to create efficient protocols for targeting such intracellular organ-
elles is augmented (Torchilin 2006 ).
Trafficking substances inside cells is an intrinsic process of prime importance.
As an example, it has been demonstrated that an oncogene can be transformed into
an apoptotic factor by manipulating the intracellular location of the protein, as in
the case of Bcr-Abl protein in chronic myelogenous leukemia (Kanwal et al. 2004 ).
Thus an externally introduced ligand can alter the location of an intracellular pro-
tein modifying its functionality (Kakar et al. 2007 ). Nanotechnology being in the
interface of a variety of disciplines on the microscopic and molecular scales pro-
vides great opportunities to manipulate trafficking of the substances specifically to
the target organelles. A number of nanocarriers have been evaluated for the ability
to deliver the substances to different subcellular compartments. These include lipid
based systems (liposomes, ethosomes), magnetic nanoparticles, polymeric carriers
(drug conjugates, micelles, nanoparticles). The different systems, their form fac-
tors, and targeting mechanism are summarized in Table 3 .
Prokop and Davidson, have discussed the emergence of nanovehicular (NV)
intracellular delivery systems which differ from microdelivery and commercially
employed nanotechnology. NVs are created to deliver cargo to particular intracel-
lular sites, and if possible, exert a local action that may range over a wide scale
of nanosizes (Prokop and Davidson 2008 ). Intracellular targeting such as endo-
lysosomal, cytoplasmic, nuclear and mitochondrial trafficking can be achieved
using nanovectors with specific physical characteristics as carriers.