Similar accumulation profiles between CDNs and exosomes
were observed in an in vivo biodistribution study using mouse
xenograft model of colon carcinoma (Fig. 5d), indicating that
CDNs were able to mimic the endogenous exosomes [29]. These
data confirm the ability of CDNs and exosomes to accumulate at
the diseased area (in this case the tumor tissue). On the other hand,
we also confirmed the intrinsic targeting abilities of monocytederived CDNs towards cancer cells rather than healthy cells. It
was observed that doxorubicin-loaded CDNs reduced the viability
of HeLa cells (a cancer cell line) more than the co-cultured
HEK293 cells (a non-cancer cell line). This is in contrast to the
effect of free doxorubicin, where the cell viability of both cell lines
was reduced to a similar extent. Indeed, the results further exemplify the cancer targeting potential of CDNs, in both monocultures
and co-cultures, an effect we attributed to the retention of original
monocytes’ membrane surface from which the CDNs were
derived [40].
All in all, though exosomes and exosome-mimetics hold tremendous potential in the development of novel targeting DDSs,
there are challenges associated with drug loading, in vivo clearance,
and possible immunogenic effects. First, relatively poor loading was
observed when CDNs were loaded with doxorubicin (encapsulation efficiency (EE%) ~17%) [40], compared to the synthetic liposomes (with EE% for doxorubicin >90%) [42]. This has prompted
researchers and scientists to extend their exploration and develop
various types of bioinspired DDSs (Table 4). Examples of bioinspired
DDSs.). Among them, hybrid systems obtained from the fusion of
synthetic and cell-derived components have gained much interest
in recent years, as a potential solution to circumvent the challenges
faced by cell-derived DDSs. By combining the more established
synthetic DDS with the nascent cell-derived DDS, these hybrid
DDSs aim to exploit the benefits of both systems and to compensate on each other’s short-comings. One of these hybrid DDSs
includes EXOPLEXs, a chimeric system formed from fusion of
CDNs and synthetic lipids (Fig. 6), which showed an EE% of
doxorubicin >65% [40, 41]. EXOPLEXs were able to retain the
characteristic protein markers of CDNs and doxorubicin-loaded
EXOPLEXs displayed an improved cancer killing effect compared
to doxorubicin-loaded liposomes.
Second, one of the lessons learnt from the in vivo study of
unmodified exosomes was their rapid clearance: these unmodified
exosomes were subjected to rapid clearance from the blood circulation (half-life about 2 min) upon intravenous administration. Studies found that these exosomes were rapidly sequested in spleen,
liver, and lungs [43, 44] when administrated intravenously, whereas
they were retained in the tumor when administrated intratumorly
[45]. This suggests that, in order to exploit the intrinsic targeting
abilitiy of exosomes and exosome-mimetics upon i.v. injection,
Exosome-Mimetics For Drug Delivery
157
were observed in an in vivo biodistribution study using mouse
xenograft model of colon carcinoma (Fig. 5d), indicating that
CDNs were able to mimic the endogenous exosomes [29]. These
data confirm the ability of CDNs and exosomes to accumulate at
the diseased area (in this case the tumor tissue). On the other hand,
we also confirmed the intrinsic targeting abilities of monocytederived CDNs towards cancer cells rather than healthy cells. It
was observed that doxorubicin-loaded CDNs reduced the viability
of HeLa cells (a cancer cell line) more than the co-cultured
HEK293 cells (a non-cancer cell line). This is in contrast to the
effect of free doxorubicin, where the cell viability of both cell lines
was reduced to a similar extent. Indeed, the results further exemplify the cancer targeting potential of CDNs, in both monocultures
and co-cultures, an effect we attributed to the retention of original
monocytes’ membrane surface from which the CDNs were
derived [40].
All in all, though exosomes and exosome-mimetics hold tremendous potential in the development of novel targeting DDSs,
there are challenges associated with drug loading, in vivo clearance,
and possible immunogenic effects. First, relatively poor loading was
observed when CDNs were loaded with doxorubicin (encapsulation efficiency (EE%) ~17%) [40], compared to the synthetic liposomes (with EE% for doxorubicin >90%) [42]. This has prompted
researchers and scientists to extend their exploration and develop
various types of bioinspired DDSs (Table 4). Examples of bioinspired
DDSs.). Among them, hybrid systems obtained from the fusion of
synthetic and cell-derived components have gained much interest
in recent years, as a potential solution to circumvent the challenges
faced by cell-derived DDSs. By combining the more established
synthetic DDS with the nascent cell-derived DDS, these hybrid
DDSs aim to exploit the benefits of both systems and to compensate on each other’s short-comings. One of these hybrid DDSs
includes EXOPLEXs, a chimeric system formed from fusion of
CDNs and synthetic lipids (Fig. 6), which showed an EE% of
doxorubicin >65% [40, 41]. EXOPLEXs were able to retain the
characteristic protein markers of CDNs and doxorubicin-loaded
EXOPLEXs displayed an improved cancer killing effect compared
to doxorubicin-loaded liposomes.
Second, one of the lessons learnt from the in vivo study of
unmodified exosomes was their rapid clearance: these unmodified
exosomes were subjected to rapid clearance from the blood circulation (half-life about 2 min) upon intravenous administration. Studies found that these exosomes were rapidly sequested in spleen,
liver, and lungs [43, 44] when administrated intravenously, whereas
they were retained in the tumor when administrated intratumorly
[45]. This suggests that, in order to exploit the intrinsic targeting
abilitiy of exosomes and exosome-mimetics upon i.v. injection,
Exosome-Mimetics For Drug Delivery
157