253
Trotta et al. reported a one-step synthesis of a new class of
GSH-responsive nanosponges (GSH-NSs) that are able to host
and to release anticancer drugs in the presence of GSH at concentrations similar to those found in chemoresistant cancer cells. The
synthesis was achieved in high yield by reacting commercially available and inexpensive 2-hydroxyethyl disulfide in the presence of
β-cyclodextrin and a suitable amount of the cross-linking agent
pyromellitic dianhydrides. The reaction was fast and complete in
few minutes at room temperature. GSH-NSs with different disulfide bridge content were easily obtained by varying the amount of
2-hydroxyethyl disulfide in the reaction mixture. Simple Soxhlet
extraction with acetone for few hours gave clean GSH-NSs [42].
Doxorubicin was chosen as a drug model to test the loading
capacities of GSH-NS and the responsiveness to GSH at intracellular concentrations, particularly as unmodified β-cyclodextrin
does not form inclusion complexes with doxorubicin. GSH-NS
(B) was selected and underwent further formulation studies. The
doxorubicin interaction with GSH-NSs was confirmed by DSC;
absence of the drug melting peak indicates that it is molecularly
dispersed within the matrix, consequently not able to crystallize.
GSH-NSs retain some of the relevant properties of unmodified
nanosponges, such as ease of internalization in cells (Fig. 1). In
vitro studies of the release of doxorubicin from GSH-NS were performed in the absence and in the presence of GSH at three different concentrations (10, 25, 50 mM). Results indicated that
doxorubicin release was enhanced in the presence of GSH, which
induced the rupture and reduction of the disulfide bridges to thiol
groups. Indeed, the in vitro release kinetics were markedly influenced by the disulfide group content in the nanosponge. The biological effect of GSH-NS was evaluated on three cell lines HCT-15,
HepG-2, and A2780, having the GSH concentration in the order
HepG-2 > HCT15 > A2780. Results suggest that GSH-NSs not
only are internalized faster than doxorubicin alone, but seem to
protect the drug from inactivation or extrusion, thus rendering the
low drug doses more effective for a longer time. Furthermore,
doxorubicin-loaded GSH-NSs displayed more apparent effects
than the free drug in cell lines having increased concentrations of
GSH [42].
Doxorubicin-loaded (Dox-GSH-NS) high effectiveness with
respect to Dox has been confirmed by in vivo experiments, performed in mice transplanted with DU145 cells. Not only were they
more effective than Dox in reducing tumor growth, in terms of
tumor weight, but also Dox-GSH-NS highly reduced the number
of proliferating Ki67-positive cells, which were about 9% of total
cells in Dox-GSH-NS-treated mice, whereas this percentage
increased to 22% in Dox-treated mice and 46% in control mice.
The biodistribution of Dox-GSH-NS demonstrated that heart
accumulation of Dox-GSH-NS was significantly lower than that
Drug-Encapsulated Cyclodextrin Nanosponges
Trotta et al. reported a one-step synthesis of a new class of
GSH-responsive nanosponges (GSH-NSs) that are able to host
and to release anticancer drugs in the presence of GSH at concentrations similar to those found in chemoresistant cancer cells. The
synthesis was achieved in high yield by reacting commercially available and inexpensive 2-hydroxyethyl disulfide in the presence of
β-cyclodextrin and a suitable amount of the cross-linking agent
pyromellitic dianhydrides. The reaction was fast and complete in
few minutes at room temperature. GSH-NSs with different disulfide bridge content were easily obtained by varying the amount of
2-hydroxyethyl disulfide in the reaction mixture. Simple Soxhlet
extraction with acetone for few hours gave clean GSH-NSs [42].
Doxorubicin was chosen as a drug model to test the loading
capacities of GSH-NS and the responsiveness to GSH at intracellular concentrations, particularly as unmodified β-cyclodextrin
does not form inclusion complexes with doxorubicin. GSH-NS
(B) was selected and underwent further formulation studies. The
doxorubicin interaction with GSH-NSs was confirmed by DSC;
absence of the drug melting peak indicates that it is molecularly
dispersed within the matrix, consequently not able to crystallize.
GSH-NSs retain some of the relevant properties of unmodified
nanosponges, such as ease of internalization in cells (Fig. 1). In
vitro studies of the release of doxorubicin from GSH-NS were performed in the absence and in the presence of GSH at three different concentrations (10, 25, 50 mM). Results indicated that
doxorubicin release was enhanced in the presence of GSH, which
induced the rupture and reduction of the disulfide bridges to thiol
groups. Indeed, the in vitro release kinetics were markedly influenced by the disulfide group content in the nanosponge. The biological effect of GSH-NS was evaluated on three cell lines HCT-15,
HepG-2, and A2780, having the GSH concentration in the order
HepG-2 > HCT15 > A2780. Results suggest that GSH-NSs not
only are internalized faster than doxorubicin alone, but seem to
protect the drug from inactivation or extrusion, thus rendering the
low drug doses more effective for a longer time. Furthermore,
doxorubicin-loaded GSH-NSs displayed more apparent effects
than the free drug in cell lines having increased concentrations of
GSH [42].
Doxorubicin-loaded (Dox-GSH-NS) high effectiveness with
respect to Dox has been confirmed by in vivo experiments, performed in mice transplanted with DU145 cells. Not only were they
more effective than Dox in reducing tumor growth, in terms of
tumor weight, but also Dox-GSH-NS highly reduced the number
of proliferating Ki67-positive cells, which were about 9% of total
cells in Dox-GSH-NS-treated mice, whereas this percentage
increased to 22% in Dox-treated mice and 46% in control mice.
The biodistribution of Dox-GSH-NS demonstrated that heart
accumulation of Dox-GSH-NS was significantly lower than that
Drug-Encapsulated Cyclodextrin Nanosponges