Chemistry Reference
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has been manipulated in drug delivery to the cytosolic space, cellular compo-
nents such as endosomes, lysosomes, endoplasmic reticulum, and mitochon-
dria, and tumors. The reduction of disulfi de linkages can also be a consequence
of exposure to a reductase enzyme. Entry of molecules to these compartments
is limited to small molecules; however, techniques have been developed to
overcome this, including the use of liposomes. In liposomal drug delivery
strategies, disulfi des act as linkers for targeting conjugates (Ishida et al., 2001;
Kirpotin et al., 1996; Zhang et al., 2004) or as disulfi de - bridged lipids (Bhavane
et al., 2003; Karathanasis et al., 2005), which are critical to liposome stability.
Kirpotin et al. synthesized a disulfi de-linked PEG conjugate that had two
functions in two different approaches with these materials; fi rst, thiolytic cleav-
age led to destabilization of the vesicle and release of its content, and second
it provided pH sensitivity in the system (Kirpotin et al., 1996). Karathanasis
and co-workers (2005) have made cross-linked liposomes toward creating a
drug delivery system suitable for nebulization for inhalation delivery. These
modifi ed liposomes are cleavable on exposure to cysteine, thereby altering the
size distribution and stimulating drug release.
Lipid self-assembled systems have not been commonly reported in which
responsiveness to ionic or osmotic variation are used to stimulate self-assembly
changes leading to control over drug release. These two stimuli present an
interesting option for controlling self-assembled systems, as pressure and ionic
strengths are known to affect the internal packing of the amphiphiles (Czeslik
et al., 1995; Greaves and Drummond, 2008; Winter et al., 1999; Yaghmur et al.,
2009). A possible application of pressure dependence of a drug delivery system
could arise in the treatment of eye conditions such as glaucoma, where the
“intelligent” drug delivery system could act as a sensor to changes in intraocu-
lar pressure and so automatically adjust the release of an encapsulated drug.
The pressure is elevated inside tumor tissues due to compromised lymphatic
drainage that also presents an albeit limited opportunity for using pressure as
a trigger for drug release from such systems (Baxter and Jain, 1990).
The addition of specifi c ions or change in counterions has been reported as
a means by which to manipulate lipid self-assembly and hence could be used
as a drug release trigger. Shen reported that the self-assembly of an amphi-
philic ionic liquid that forms micelles in water was disrupted on exchange of
the bromide counterion with hexafl uorophosphate, with subsequent dye
release (Shen et al., 2008). Yaghmur et al. have demonstrated a direct vesicle
to inverted hexagonal phase transition for mixtures of glyceryl monooleate
and dioleyl phosphatidyl glycerol when exposed to increasing concentration
of calcium ions (Yaghmur et al., 2008b). The divalent counterion reduced the
apparent area of the head group, leading to a change in molecular packing
and subsequent phase transition. Although not resulting in a change in self-
assembly behavior, the release of a cationic ruthenium complex, “rubipy,” from
cubic phase on addition of NaCl to the aqueous compartment was demon-
strated when the glyceryl monooleate cubic phase contained a small amount
of oleic acid (Clogston and Caffrey, 2005). The shielding of the electrostatic
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