Ambisome
® ) [2]. Of note, liposomes are one of the most extensively studied DDSs among the synthetic DDSs (e.g., polymeric
micelles, metal nanoparticles, and carbon nanotubes), with wellestablished production protocols, drug loading procedures, and
physical characterization methods.
This might seem surprising, since the mechanism by which
liposomes accumulate at the target sites (such as tumor or inflammatory sites) is in common with other nanoscaled DDSs, and based
on the so-called Enhanced Permeability and Retention (EPR)
effect. This phenomenon, characterized by the “leaky” blood vessels with increased vascular permeability (with fenestrations
between 0.2 and 1.2 μm) [3] at the diseased area, in contrast to
the tight endothelial junctions of normal vessels (only up to about
10 nm) [4], is exploited by the nanometric dimensions of the
nanocarriers (irrespective of the material used) and their ability to
remain in the bloodstream for long time, rather than depending on
the specific nature of the liposomes. Hence, liposomes do not
possess any specific intrinsic targeting capability; on the contrary,
they need to be further decorated at their surface (usually with poly
(ethylene) glycol (PEG)) to avoid recognition and premature clearance by the mononuclear phagocyte system (MPS). Furthermore,
not all target sites are susceptible to the EPR effect, as is the case of
low-EPR tumors (e.g., pancreatic and bladder cancers) [5] and
some target sites in the poor perfusion regions of the body
[6]. Additionally, the inter- and intra-patient heterogeneities
observed in the clinical settings also limit the effectiveness of this
“passive targeting” (a.k.a. EPR-mediated targeting). Although
much effort is devoted to employ ligands (e.g., peptides or antibodies) at the surface of nanoparticles to confer certain specificity
through “active targeting,” there has been only limited clinical
success [7, 8].
The complex issue surrounding the practicality of nanoparticles
as DDSs extends to the limited cellular uptake of liposomes by
target cells or the potential elicitation of immune responses (e.g.,
complement activation-related pseudoallergies (CARPA) attributed to the synthetic lipid components or accelerated blood clearance (ABC) related to the generation of specific antibodies), which
decrease the efficacy of liposomes upon repeated use in the clinical
setting [9].
In recent years, cell-derived DDSs or extracellular nanovesicles
have attracted growing interest and have been increasingly explored
as novel platforms for drug delivery due to their intrinsic targeting
ability [10, 11] . Among all cell-derived DDSs, exosomes (i.e.,
nanovesicles secreted endogenously by cells) are the most
promising candidates due to their nanodimension (with size
<300 nm, which enables them to exploit the EPR effect) [6, 12]
and their recently discovered role in cell-to-cell communication
(which is associated with a specific cellular uptake) [13, 14].
148
Yi-Hsuan Ou et al.
® ) [2]. Of note, liposomes are one of the most extensively studied DDSs among the synthetic DDSs (e.g., polymeric
micelles, metal nanoparticles, and carbon nanotubes), with wellestablished production protocols, drug loading procedures, and
physical characterization methods.
This might seem surprising, since the mechanism by which
liposomes accumulate at the target sites (such as tumor or inflammatory sites) is in common with other nanoscaled DDSs, and based
on the so-called Enhanced Permeability and Retention (EPR)
effect. This phenomenon, characterized by the “leaky” blood vessels with increased vascular permeability (with fenestrations
between 0.2 and 1.2 μm) [3] at the diseased area, in contrast to
the tight endothelial junctions of normal vessels (only up to about
10 nm) [4], is exploited by the nanometric dimensions of the
nanocarriers (irrespective of the material used) and their ability to
remain in the bloodstream for long time, rather than depending on
the specific nature of the liposomes. Hence, liposomes do not
possess any specific intrinsic targeting capability; on the contrary,
they need to be further decorated at their surface (usually with poly
(ethylene) glycol (PEG)) to avoid recognition and premature clearance by the mononuclear phagocyte system (MPS). Furthermore,
not all target sites are susceptible to the EPR effect, as is the case of
low-EPR tumors (e.g., pancreatic and bladder cancers) [5] and
some target sites in the poor perfusion regions of the body
[6]. Additionally, the inter- and intra-patient heterogeneities
observed in the clinical settings also limit the effectiveness of this
“passive targeting” (a.k.a. EPR-mediated targeting). Although
much effort is devoted to employ ligands (e.g., peptides or antibodies) at the surface of nanoparticles to confer certain specificity
through “active targeting,” there has been only limited clinical
success [7, 8].
The complex issue surrounding the practicality of nanoparticles
as DDSs extends to the limited cellular uptake of liposomes by
target cells or the potential elicitation of immune responses (e.g.,
complement activation-related pseudoallergies (CARPA) attributed to the synthetic lipid components or accelerated blood clearance (ABC) related to the generation of specific antibodies), which
decrease the efficacy of liposomes upon repeated use in the clinical
setting [9].
In recent years, cell-derived DDSs or extracellular nanovesicles
have attracted growing interest and have been increasingly explored
as novel platforms for drug delivery due to their intrinsic targeting
ability [10, 11] . Among all cell-derived DDSs, exosomes (i.e.,
nanovesicles secreted endogenously by cells) are the most
promising candidates due to their nanodimension (with size
<300 nm, which enables them to exploit the EPR effect) [6, 12]
and their recently discovered role in cell-to-cell communication
(which is associated with a specific cellular uptake) [13, 14].
148
Yi-Hsuan Ou et al.