3 research outputs found
Cyclometalated Iminophosphorane Gold(III) and Platinum(II) Complexes. A Highly Permeable Cationic Platinum(II) Compound with Promising Anticancer Properties
New
organometallic goldÂ(III) and platinumÂ(II) complexes containing
iminophosphorane ligands are described. Most of them are more cytotoxic
to a number of human cancer cell lines than cisplatin. Cationic PtÂ(II)
derivatives <b>4</b> and <b>5</b>, which differ only in
the anion, Hg<sub>2</sub>Cl<sub>6</sub><sup>2â</sup> or PF<sub>6</sub><sup>â</sup> respectively, display almost identical
IC<sub>50</sub> values in the sub-micromolar range (25â335-fold
more active than cisplatin on these cell lines). The gold compounds
induced mainly caspase-independent cell death, as previously reported
for related cycloaurated compounds containing IM ligands. Cycloplatinated
compounds <b>3</b>, <b>4</b>, and <b>5</b> can also
activate alternative caspase-independent mechanisms of death. However,
at short incubation times cell death seems to be mainly caspase dependent,
suggesting that the main mechanism of cell death for these compounds
is apoptosis. Mercury-free compound <b>5</b> does not interact
with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies
of <b>5</b> by two different assays, <i>in vitro</i> Caco-2 monolayers and a rat perfusion model, have revealed a high
permeability profile for this compound (comparable to that of metoprolol
or caffeine) and an estimated oral fraction absorbed of 100%, which
potentially makes it a good candidate for oral administration
Cyclometalated Iminophosphorane Gold(III) and Platinum(II) Complexes. A Highly Permeable Cationic Platinum(II) Compound with Promising Anticancer Properties
New
organometallic goldÂ(III) and platinumÂ(II) complexes containing
iminophosphorane ligands are described. Most of them are more cytotoxic
to a number of human cancer cell lines than cisplatin. Cationic PtÂ(II)
derivatives <b>4</b> and <b>5</b>, which differ only in
the anion, Hg<sub>2</sub>Cl<sub>6</sub><sup>2â</sup> or PF<sub>6</sub><sup>â</sup> respectively, display almost identical
IC<sub>50</sub> values in the sub-micromolar range (25â335-fold
more active than cisplatin on these cell lines). The gold compounds
induced mainly caspase-independent cell death, as previously reported
for related cycloaurated compounds containing IM ligands. Cycloplatinated
compounds <b>3</b>, <b>4</b>, and <b>5</b> can also
activate alternative caspase-independent mechanisms of death. However,
at short incubation times cell death seems to be mainly caspase dependent,
suggesting that the main mechanism of cell death for these compounds
is apoptosis. Mercury-free compound <b>5</b> does not interact
with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies
of <b>5</b> by two different assays, <i>in vitro</i> Caco-2 monolayers and a rat perfusion model, have revealed a high
permeability profile for this compound (comparable to that of metoprolol
or caffeine) and an estimated oral fraction absorbed of 100%, which
potentially makes it a good candidate for oral administration
Gated Mesoporous Silica Nanocarriers for a âTwo-Stepâ Targeted System to Colonic Tissue
Colon targeted drug delivery is highly
relevant not only to treat
colonic local diseases but also for systemic therapies. Mesoporous
silica nanoparticles (MSNs) have been demonstrated as useful systems
for controlled drug release given their biocompatibility and the possibility
of designing gated systems able to release cargo only upon the presence
of certain stimuli. We report herein the preparation of three gated
MSNs able to deliver their cargo triggered by different stimuli (redox
ambient (<b>S1</b>), enzymatic hydrolysis (<b>S2</b>),
and a surfactant or being in contact with cell membrane (<b>S3</b>)) and their performance in solution and <i>in vitro</i> with Caco-2 cells. Safranin O dye was used as a model drug to track
cargo fate. Studies of cargo permeability in Caco-2 monolayers demonstrated
that intracellular safranin O levels were significantly higher in
Caco-2 monolayers when using MSNs compared to those of free dye. Internalization
assays indicated that <b>S2</b> nanoparticles were taken up
by cells via endocytosis. <b>S2</b> nanoparticles were selected
for <i>in vivo</i> tests in rats. For <i>in vivo</i> assays, capsules were filled with <b>S2</b> nanoparticles
and coated with Eudragit FS 30 D to target colon. The enteric coated
capsule containing the MSNs was able to deliver <b>S2</b> nanoparticles
in colon tissue (first step), and then nanoparticles were able to
deliver safranin O inside the colonic cells after the enzymatic stimuli
(second step). This resulted in high levels of safranin O in colonic
tissue combined with low dye levels in plasma and body tissues. The
results suggested that this combination of enzyme-responsive gated
MSNs and enteric coated capsules may improve the absorption of drugs
in colon to treat local diseases with a reduction of systemic effects