Biomedical Engineering Reference
In-Depth Information
membrane fusion, and displays mitochondriotropic features (Biasutto et al.
2010
;
Fujiwara et al.
2010
; Yamada et al.
2007
; Rapoport and Lorberboum-Galski
2009
).
Similarly, Mito-8, a mitochondria-selective peptide fused to QDs was able to
induce a strong mitochondrial localization in living cells (Hoshino et al.
2004a
).
Finally, Pluronic® block copolymers exhibit the ability to reach the mitochondria,
where they exert unique pharmacological activities, such as ATP depletion in
multidrug resistant cancer cells (Sahay et al.
2010b
; Gupta et al.
2010
).
4.6
Nuclear Targeting
The nucleus is a membrane-enclosed organelle that houses the cell's genetic material.
The outer nuclear membrane is continuous with the ER. Nuclear pores, approxi-
mately 9 nm in diameter, allow certain molecules to enter the nucleus, making the
nucleoplasm topologically equivalent to the cytosol. The nucleolus is a dense struc-
ture of highly packed heterochromatin that resides within the nucleus. The nucleus
is involved in three major functions: nucleic acid compartmentalization and storing
of the genetic material; DNA replication, transcription and cell replication; and
processing of pre-mRNA (e.g. splicing).
The Nuclear Pore Complex (NPC) is a transport channel in the nuclear mem-
brane (a double lipid bilayer) composed of nucleoporins. The NPC regulates traf-
ficking of water-soluble macromolecules, such as proteins, carbohydrates, lipids
and ribosomes between the nucleus and the cytoplasm in a signal-dependent man-
ner. It has an inner (functional) diameter of 9 nm and an outer diameter of 120 nm.
The NPC can dilate to facilitate the bidirectional translocation of a wide size range
of protein complexes. Small particles (<30 kDa) are able to pass through the NPC
by passive diffusion. Larger particles require a Nuclear Localization Signal (NLS)
to cross. Aside from the standard cellular barriers to entry as mentioned earlier,
internalization through the nuclear pore represents a unique barrier to nuclear tar-
geting. Nature provides some solutions to circumventing the barriers. For example,
viruses utilize various proteins to navigate intracellular trafficking mechanisms and
localize to the nucleus. These viral models serve as the basis for the design of some
targeted, functionalized nanoparticles (Mao et al.
2010
).
Targeting the nucleus is of great importance due to its key resident: DNA.
Multiple diseases, including cancer and genetic disease, arise from nuclear mal-
function, DNA damage and mutation. Many cancer drugs target the nucleus to
inhibit or interfere with cell replication. Nanoparticles containing certain cancer
therapeutics target the cytoplasm and rely on diffusion of the drug through the
nuclear pore for therapeutic action. For drugs that cannot cross through the pores,
direct nuclear targeting of nanoparticles may be able to increase transport into the
nucleus. The most extensively exploited way to target nanoparticles to the nucleus
is through surface conjugation to a NLS. NLSs consist of one or more short
sequences of positively charged lysine (K) or arginine (R) residues. A protein trans-
lated with a NLS will bind strongly to importin alpha/beta, and this complex will
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