Biomedical Engineering Reference
In-Depth Information
that the size of the carrier might determine its intracellular fate. While micron-size
carriers had prolonged residency in prelysosomal compartments, submicron carriers
trafficked more readily to lysosomes (Muro et al.
2008
).
In addition to endolysosomal targeting there is a growing body of work that
suggests the feasibility of modifying nanocarriers to redirect delivery of their cargo
to other sub-cellular compartments. A fusigenic viral liposome fused with the
Hemagglutinating virus of Japan (HVJ) envelope protein was used to efficiently
encapsulate and deliver DNA to the cytoplasm through fusion of the liposome with
the plasma membrane (Dzau et al.
1996
). In another study, pH sensitive liposomes
composed of dioleylphosphatidylethanolamine and cholestryl hemisuccinate have
been reported to be efficient carriers of N-butylnojirimycin to the endoplasmic
reticulum (ER) (Costin et al.
2002
); this can potentially be applied to the treatment
of melanoma. Surface functionalization with ligands like cholera toxin, shiga toxin
due to which the nanocarrier will be internalized into the cell by caveolae or lipid
raft mediated endocytosis surpasses the lysosome and delivers the moiety to the ER
or golgi complex (Le and Nabi
2003
; Tarrago-Trani and Storrie
2007
). Such ER
liposomes may be used for the delivery of anti virals (Pollock et al.
2010
). On the
other hand, presence of an ER retrieval sequence on a ligand may confer to it ER
targeting abilities. Acyl coenzyme-A binding protein (ACBP) is a ligand consisting
of a potential ER retrieval signal, a dilysine (KK) motif near its C-terminus, which
was found, by live cell imaging and indirect immunohistochemistry, to preferen-
tially accumulate in the endoplasmic reticulum and the golgi complex (Hansen
et al.
2008
). Liposomes modified with mitochondriotropic ligands have been shown
to improve the efficacy of an anticancer drug both
in vitro
and
in vivo
(Boddapati
et al.
2008
). To render liposomes mitochondria-specific, the liposomal surface was
modified with triphenyl phosphonium (TPP) cations (Boddapati et al.
2005
).
Methyltriphenylphosphonium cations (MTPP) are rapidly taken up by mitochon-
dria in living cells (Liberman et al.
1969
) and have been extensively explored for
the delivery of biological active molecules to and into mitochondria (Murphy
2008
;
Murphy and Smith
2007
; Ross et al.
2008
; Smith et al.
2003
). The replacement of
the methyl group in MTPP with a stearyl residue was shown to facilitate the attach-
ment of TPP cations to the surface of liposomes (Boddapati et al.
2005
).
Solid nanoparticles prepared from polymers or colloidal metals also fall under
the umbrella of pharmaceutical nanocarriers. Gold nanoparticles (AuNPs) are a
flexible nanoscale platform for the conjugation of a variety of targeting ligands
based on the affinity of thiol and amino groups for the gold surface. Of particular
interest here is the report of the conjugation of the triphenyl phosphonium mito-
chondriotropic ligand (Horobin et al.
2007
) to the surface of AuNPs (Ju-Nam et al.
2006
). Triphenyl-phosphonioalkylthiosulfate and potassium tetrachloroaurate were
dissolved in dichloromethane followed by drop-wise addition into an aqueous solu-
tion of sodium borohydride to generate 5-10 nm sized AuNPs with surface-attached
triphenylphosphonium residues. While data describing the intracellular localization
of these potentially mitochondriotropic AuNP's have not yet been made available,
AuNPs have already been targeted to the nucleus using the adenoviral nuclear
localization signal (NLS) and integrin binding domain (Tkachenko et al.
2004
).
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