Biomedical Engineering Reference
In-Depth Information
phospholipid vesicles with sizes varying from 50 to 1,000 nm and greater, which
can be loaded with a variety of drugs (Lasic
1993
; Torchilin
2005b
). Further, the
addition of a polyethylene glycol (PEG) coating renders these liposomes long-
circulating (Lasic and Martin
1995
), which allows them to accumulate in various
pathological areas with compromised (leaky) vasculature, such as tumors or
infarcts. It has been shown that (Torchilin et al.
1996
) the long-circulating lipo-
somes can be made 'targeted', if antibodies or other specific binding molecules
(ligands) have been attached to the water-exposed tips of the PEG chains
(Torchilin et al.
2001a
).
Micelles, including polymeric micelles, are also a popular and well-investigated
pharmaceutical carrier due to their small size (10-100 nm),
in vivo
stability, ability
to solubilize water insoluble anticancer drugs, and prolonged blood circulation
times (Torchilin
2001, 2007a
). The typical core-shell structure of polymeric
micelles is formed by the self-assembly of amphiphilic block-copolymers consisting
of hydrophilic and hydrophobic monomer units in aqueous media (Torchilin
2001
).
The use of special amphiphilic molecules as micelle-building blocks can also intro-
duce the property of micelle extended blood half-life. Block-copolymer micelles
can also be used to target their payload to specific tissues through either passive or
active means. The passive targeting is due to the small micellar size which allows
in spontaneous penetration into the interstitium of body compartments with a leaky
vasculature (tumors and infarcts) by the enhanced permeability and retention (EPR)
effect (Maeda et al.
2000
; Torchilin
2001, 2007a
; Maeda et al.
2009
; Lukyanov
et al.
2004
). Active targeting of micelles can also be achieved by attachment of
target-specific ligands to their surface (Torchilin
2001, 2007a
).
We have been specifically interested in micelles made of PEG-phosphatidyl etha-
nolamine (PEG-PE), where, the use of lipid moieties as hydrophobic blocks capping
hydrophilic polymer (such as PEG) chains provides the additional advantage of par-
ticle stability when compared with conventional amphiphilic polymer micelles due to
the existence of two fatty acid acyls, which contribute considerably to an increase in
the hydrophobic interactions between the polymeric chains of the micelle core
(Lukyanov and Torchilin
2004
). Such PEG-PE micelles demonstrate good stability,
longevity in the blood and the ability to accumulate in the areas with a damaged or
leaky vasculature (Lukyanov et al.
2004
; Lukyanov and Torchilin
2004
).
The liposomes and micelles can be assembled in 'modular fashion' by addition
of various components such as cationic lipids, intracellular peptide-conjugated
lipids, ligand-modified lipids and organelle-targeted lipid conjugates for tumor
targeted or intracellular delivery. Various components of these 'modular system'
can be further incorporated in one carrier (either liposomes or micelles) to build a
'multifunctional system' (e.g. combination of cell penetrating function, cancer cell
targeting antibody and stimuli-sensitivity in one system) to perform various func-
tions simultaneously or in orchestrated fashion.
In this review, we will discuss the approaches successfully developed in our
laboratory for intracellular delivery of liposomes and lipid-core micelles, particu-
larly, the use of cationic lipids, cell penetrating peptides (CPPs), and organelle-
targeting ligands.
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