Three metal complexes[Re(bpy)(CO)3(CN-t-Bu)]Cl (1) (where bpy = 2,2-bipyridine), Bu4N[Ir(ppy)2(CN)2] (2), and Ir(ppy)3 (3) (where ppy = 2-phenylpyridine and Bu4N = tetrabutylammonium cation)were evaluated as oxygen sensors in poly((n-butylamino)thionylphosphazene) (nBuPTP) matrixes. The
phosphorescent dyes 2 and 3 exhibit long lifetimes and high quantum yields in degassed dichloromethane
and toluene solutions and when dissolved in the polymer matrix. These two dyes exhibited exponential
decays both in solution and in the polymer films, with somewhat longer lifetimes (for 2, τ0 = 4.78 μs;
for 3, τ0 = 1.40 μs) in the polymer film. All three dyes gave linear Stern−Volmer plots, but 1 was rather
sensitive to photodecomposition. The slopes of the Stern−Volmer plots for these dyes were compared to
those measured previously for platinum octaethyl porphine (PtOEP) and ruthenium tris-diphenylphenanthroline chloride ([Ru(dpp)3]Cl2. Attempts to explain the differences in slope using τ0 as the sole scaling
parameter were unsuccessful. To explain these results, we calculated the effective capture radius for
quenching by oxygen, which was 1.7 nm for 2 and 2.7 nm for 3, relative to a value of 1.0 nm for PtOEP.
Thus, dye 3 is 2.7 times more sensitive to quenching by oxygen than PtOEP and more than 5 times more
sensitive than [Ru(dpp)3]Cl2.
The onset of multidrug resistance (MDR) in ovarian cancer is one of the main causes of treatment failure and low survival rates. Inadequate drug exposure and treatment-free periods due to intermittent chemotherapy select for cancer cells overexpressing drug efflux transporters, resulting in resistant disease. The present study examines the sustained administration of the chemotherapeutic agent docetaxel (DTX) alone and in combination with cepharanthine (CEP), a potent drug efflux transporter inhibitor. DTX and CEP were delivered via the intraperitoneal route in a sustained manner using an injectable polymer-lipid formulation. In vitro, the combination strategy resulted in significantly (p < 0.05) more apoptosis, greater intracellular accumulation of DTX, and lower DTX efflux in ovarian cancer cells showing the MDR phenotype. In vivo, sustained treatment with DTX and CEP showed significantly greater (p< 0.05) tumor inhibition (91 ± 4%) in a murine model of multidrug resistant ovarian cancer compared to sustained DTX treatment (76 ± 6%) and was more than twice as efficacious as intermittent DTX treatment. Overall findings from these studies highlight the impact of sustained delivery of monotherapy and combination therapy in the management of refractory ovarian cancer displaying the MDR phenotype.
Star copolymers (SCPs) have recently attracted considerable attention due to their unique applicability in a wide range of biomedical fields. With the intention of rationally designing a stable unimolecular SCP, atomistic molecular dynamics simulations of thirteen SCPs are conducted. The SCPs each have six identical arms of methoxypoly(ethylene glycol)-b-polycaprolactone (MePEG x -b-PCL y ) and systematically vary in terms of total molecular weight and ratio of hydrophobic to hydrophilic block length. For all hydrated SCPs, the simulations predict a densely packed hydrophobic PCL core that excludes water and is phase separated from a highly mobile hydrophilic PEG corona. The radii of the hydrophobic PCL core and the PEG blocks are independent of each other and can be predicted over a broad molecular weight range. A linear relationship between the hydration and the molecular weight of the PEG blocks is observed with the average number of water molecules bound per PEG repeat unit within the range of that determined experimentally. As well, a quantitative relationship relates the water accessed surface area of the hydrophobic PCL core to the molecular weights of PCL and PEG moieties. We postulate that the propensity for aggregation of SCPs into multimolecular micelles is correlated with the partial hydration of the hydrophobic core of unimers. Our results suggest that SCPs with a hydrophobic PCL core #2 kDa per arm are fully protected from water when the hydrophilic PEG blocks approach 14.6 kDa per arm. We therefore predict that SCPs of this composition yield unimolecular micelles that are thermodynamically stable at low concentrations.
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