Biomedical Engineering Reference
In-Depth Information
internalization and localization within organelles. Although the toxins alone pass
through the Golgi/ER, the toxin-QD conjugates tend to accumulate in endosomes
(Tekle et al.
2008
; Sandvig et al.
2010
). Pluronic or poloxamer utilizes similar path-
ways as pathogens to gain entry into the cell. Sahay notes that the polymer bypasses
endosomes/lysosomes and enters a transient co-localization with the ER before the
polymer localizes to the mitochondria (Sahay et al.
2010b
). Ma et al. study the inter-
nalization and localization of a recombinant peptide containing the KDEL motif,
which appears to localize to the ER (Motosugi et al.
2009
). Others use fluorescent
protein-conjugates with -KDEL to fluorescently tag the organelle. Most non-modified
nanoparticles have shown little to no localization with the Golgi/ER. Lai et al. show
that negatively charged 43 nm polymer nanoparticles can enter HeLa cells through
clathrin-mediated endocytosis and reside in the endo-lysosomal compartment.
Smaller particles, approximately 24 nm in size, utilize a clathrin- and caveolin-
independent pathway, bypass lysosomes and localize near the perinuclear space. In
all cases, whether the particles localize within the lumen of the ER or on the outside
membrane, has yet to be clearly and definitively shown (Lai et al.
2008
).
Some drugs attempt to aggravate the ER stress response in cancer cells to induce
apoptosis. However, as with most chemotherapeutic agents, global toxicity is
observed. Modification of nanoparticles to target tumor cells and then the target
organelle within, can better direct a chemotherapeutic drug to the specific location
necessary. The mechanism of Cholera and Shiga toxins to target the ER is well
studied (Rajendran et al.
2010
). They are sorted from the plasma membrane to the
Golgi complex through the pentameric B-subunit of the toxin. From there, the tox-
ins are retrograde sorted to the ER, in which the A subunit of the toxin is released
into the cytosol (Sandvig et al.
2010
). The B-domain of Shiga toxin (STX-B) has
been used to transport a prodrug against colon cancer to the ER, where it is released
and transported to the cytosol (Johannes and Romer
2010
). Targeting non-cancer
diseases via the ER is a field that has hardly been breached due to the relative
inability until now to specifically target the ER. Potential drugs may be used in
targeting the ER stress response, downregulating the exocytosis of proteins or drugs
(responsible for multi-drug resistance), or interacting with cholesterol (and lipid)
synthesis and modification. Future research is needed to develop drugs that include
novel targeting methods.
4.5
Mitochondria Targeting
Mitochondria are known as the “power plants” of the cells because they supply
most of the cellular ATP. In addition, they are involved in cellular signaling, dif-
ferentiation and in the control of the cell cycle. More specifically, mitochondria are
involved in the (1) storage of calcium, (2) regulation of the membrane potential, (3)
apoptosis-programmed cell death (4) calcium signaling (including calcium-evoked
apoptosis), (5) cellular proliferation regulation, (6) regulation of cellular metab-
olism, (7) certain heme synthesis reactions, (8) steroid synthesis, and (9) heat
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