252
units) was synthesized by cross-linking with epichlorohydrin (EPI).
In vivo tissue toxicity of SFN and its soluble complexes indicated
that CyD polymer/SFN complexes have lower in vivo toxicity than
SFN alone. In particular, oCyD/SFN showed the lowest toxicity
in the lung, where SFN alone showed a strong toxicity under
experimental conditions. Toxicological data was also confirmed by
a lower general toxicity of oCyD/SFN in comparison to SFN or
pCyD/SFN. Moreover, both the polymer/SFN complexes showed
almost no liver toxicity as compared to SFN. Overall results suggest that CyD polymers could provide a new formulation strategy
for the delivery of SFN in order to increase its bioavailability and
reduce its systemic toxicity [36].
ICOS is a T-cell co-stimulatory molecule involved in T-cell
function. It binds B7h expressed by several cell types including
tumor cells. ICOS interaction may modulate the spread of cancer
metastases, suggesting the novel use of ICOS-Fc as an immunomodulatory drug. In melanoma, treatment with anti-CTLA-4 Ab
induces an increase of ICOS+ effector T cells, indicating that the
ICOS/B7h pathway is required for antitumor responses. However,
in vivo administration of free ICOS-Fc solution induces only antimetastasis effects, without inhibiting the local growth of B16 cells
injected subcutaneously in mice [37].
ICOS-Fc was incorporated in β-cyclodextrin nanosponges
(NS), with the aim of increasing its delivery to the tumor, enabling
an anticancer effect. In vivo experiments were performed using the
B16 melanoma model of transplantable tumors. C57BL/6 mice
were injected subcutaneously with 105 B16-F10 cells and treated
with an i.v. injection of either the mouse ICOS-Fc, ICOS-Fc
loaded in NS, or empty NS as control. ICOS-Fc was loaded into
the NS with a good encapsulation efficiency. A slow and prolonged
in vitro release kinetics of ICOS-Fc from the nanoformulation was
observed. The loaded nanoformulation was stable for more than
6 months, protecting ICOS-Fc from degradation. In vivo experiments showed that i.v. injection of ICOS-Fc loaded in NS remarkably inhibited either the metastasis formation or the growth of
established subcutaneous B16 tumors. Interestingly, the delivery
of ICOS-Fc with NS is crucial for its therapeutic effectiveness. This
result showed that the combination of ICOS with a nanocarrier
can enhance its antitumor response [38].
New generations of stimuli-responsive materials were proposed as novel drug delivery systems for the time-controlled release
of drugs targeted to specific cells or organs by changing their conformation or chemical structure under an external stimulus, for
example, light, temperature [39] or pH [40], or biochemical stimuli, such as the presence of cellular antioxidant glutathione (GSH).
Chemoresistant tumor cells are reported to possess high levels of
GSH; its concentration inside cells (2–20 mm) is about 1000 times
higher than in plasma (2–20 mm) [41].
Maria Tannous et al.
units) was synthesized by cross-linking with epichlorohydrin (EPI).
In vivo tissue toxicity of SFN and its soluble complexes indicated
that CyD polymer/SFN complexes have lower in vivo toxicity than
SFN alone. In particular, oCyD/SFN showed the lowest toxicity
in the lung, where SFN alone showed a strong toxicity under
experimental conditions. Toxicological data was also confirmed by
a lower general toxicity of oCyD/SFN in comparison to SFN or
pCyD/SFN. Moreover, both the polymer/SFN complexes showed
almost no liver toxicity as compared to SFN. Overall results suggest that CyD polymers could provide a new formulation strategy
for the delivery of SFN in order to increase its bioavailability and
reduce its systemic toxicity [36].
ICOS is a T-cell co-stimulatory molecule involved in T-cell
function. It binds B7h expressed by several cell types including
tumor cells. ICOS interaction may modulate the spread of cancer
metastases, suggesting the novel use of ICOS-Fc as an immunomodulatory drug. In melanoma, treatment with anti-CTLA-4 Ab
induces an increase of ICOS+ effector T cells, indicating that the
ICOS/B7h pathway is required for antitumor responses. However,
in vivo administration of free ICOS-Fc solution induces only antimetastasis effects, without inhibiting the local growth of B16 cells
injected subcutaneously in mice [37].
ICOS-Fc was incorporated in β-cyclodextrin nanosponges
(NS), with the aim of increasing its delivery to the tumor, enabling
an anticancer effect. In vivo experiments were performed using the
B16 melanoma model of transplantable tumors. C57BL/6 mice
were injected subcutaneously with 105 B16-F10 cells and treated
with an i.v. injection of either the mouse ICOS-Fc, ICOS-Fc
loaded in NS, or empty NS as control. ICOS-Fc was loaded into
the NS with a good encapsulation efficiency. A slow and prolonged
in vitro release kinetics of ICOS-Fc from the nanoformulation was
observed. The loaded nanoformulation was stable for more than
6 months, protecting ICOS-Fc from degradation. In vivo experiments showed that i.v. injection of ICOS-Fc loaded in NS remarkably inhibited either the metastasis formation or the growth of
established subcutaneous B16 tumors. Interestingly, the delivery
of ICOS-Fc with NS is crucial for its therapeutic effectiveness. This
result showed that the combination of ICOS with a nanocarrier
can enhance its antitumor response [38].
New generations of stimuli-responsive materials were proposed as novel drug delivery systems for the time-controlled release
of drugs targeted to specific cells or organs by changing their conformation or chemical structure under an external stimulus, for
example, light, temperature [39] or pH [40], or biochemical stimuli, such as the presence of cellular antioxidant glutathione (GSH).
Chemoresistant tumor cells are reported to possess high levels of
GSH; its concentration inside cells (2–20 mm) is about 1000 times
higher than in plasma (2–20 mm) [41].
Maria Tannous et al.