Biomedical Engineering Reference
In-Depth Information
creates a transmembrane electrochemical gradient, which includes contributions
from both a membrane potential (negative inside) and a pH difference (acidic out-
side). The membrane potential of mitochondria
in vitro
is between 180 and 200 mV,
which is the maximum a lipid bilayer can sustain while maintaining its integrity
(Murphy
1989
). Positively charged molecules are attracted by mitochondria in
response to the highly negative membrane potential, but most charged molecules
cannot enter the mitochondrial matrix because the inner mitochondrial membrane
is impermeable to polar molecules. However, certain amphiphile compounds are
able to cross both mitochondrial membranes and accumulate in the mitochondrial
matrix in response to the negative membrane potential. It has long been known that
amphiphile compounds with delocalized cationic charge can accumulate in mito-
chondria (Weissig and Torchilin
2001
). Rhodamine 123 (Rh-123), a stain for mito-
chondria in living cells, is the best known representative of this group (Chen et al.
1982
). Mitochondrial accumulation of tetraphenylphosphonium chloride and other
cationic aryl phosphonium salts was also demonstrated (Rideout et al.
1994
). The
mitochondrial accumulation and retention of dequalinium (DQA), a single-chain
bola amphiphile with two delocalized positive charge centers was also demon-
strated (Weissig and Torchilin
2001
).
We have modified liposomes with using stearyl triphenyl phosphonium (STPP)
to render them mitochondriotropic (Boddapati et al.
2008
).
In vitro
STPP liposomes
selectively accumulated in mitochondria of living cells. Also when loaded with
ceramide as model drug, it elicited strong apoptotic response
in vivo
in 4T1 mam-
mary carcinoma tumor-bearing mice at ceramide doses as low as 6 mg/kg in com-
parison with the 36 mg/kg or higher reported with non-targeted liposomes.
Recently, we prepared a novel mitochondria-targeted liposomal drug delivery
system by the modification of the liposomal surface with Rh-123 (Biswas et al.
2010
). A novel polymer was synthesized by conjugating the mitochondriotropic
dye Rh-123, with the amphiphilic PEG-PE conjugate. The co-localization study
with stained mitochondria (Fig.
10
) as well as with the isolation of mitochondria of
the cultured cells after their treatment with Rh123-liposomes showed a high degree
of accumulation of the modified liposomes in the mitochondria.
To demonstrate that specific delivery of the drug to the desired subcellular com-
partment can significantly enhance drug action, the mitotic inhibitor, paclitaxel was
used. Paclitaxel-loaded Rh123-liposomes (PCL-Rh123-L) produced significantly
higher cytotoxicity than free paclitaxel or paclitaxel-loaded plain liposomes. An
approximately 35-40% reduction of cell survival was observed with PCL-Rh123-L
compared to non-targeted PCL formulations. Thus, Rh-123-modified liposomes
target mitochondria efficiently and can facilitate the delivery of a therapeutic pay-
load to mitochondria.
Lysosomes, acidic organelles responsible for recycling of cellular constituents,
represent another important intracellular target for diseases such as lysosomal stor-
age diseases (LSD). LSD is associated with the deficiency of certain lysosomal
enzymes, which lead to accumulation of corresponding substrates in lysosomes
(Futerman and van Meer
2004
). These diseases pose a serious medical problem
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