12 research outputs found
Paclitaxel-Loaded SCK Nanoparticles: An Investigation of Loading Capacity and Cell Killing Abilities <i>in Vitro</i>
Block copolymer nanoparticles having two different hydrodynamic
diameters (120 nm vs 50 nm) and core diameters (60 nm vs 20 nm) with
variable paclitaxel loading (5 to 20 wt % with respect to polymer
weight, 4.4 μg/mL to 21.7 μg/mL paclitaxel concentrations
in ultrapure water) were prepared for their <i>in vitro</i> cytotoxicity evaluation. Empty nanoparticles did not show any inherent
cytotoxicity even at their highest concentration, whereas paclitaxel-loaded
nanoparticles resulted in IC<sub>50</sub> values that were better
than free paclitaxel at 2 h (0.021 μM vs 0.046 μM) incubation
periods, and approximately equal to free paclitaxel at 72 h (0.004
μM vs 0.003 μM) continuous incubation. Confocal fluorescence
microscopy images demonstrated that the drug-loaded nanoparticles
internalized into KB cells within 2 h and released their payload,
resulting in cytotoxicity as evident from the fragmented nuclei present.
Functionalization of the nanoparticle surfaces with poly(ethylene
oxide) (2 kDa PEO, 5 PEO per block copolymer chain) did not affect
the loading of paclitaxel or cell kill ability. No free paclitaxel
was found in these nanoparticle formulations indicated by analytical
assays
<i>In Vitro</i> Efficacy of Paclitaxel-Loaded Dual-Responsive Shell Cross-Linked Polymer Nanoparticles Having Orthogonally Degradable Disulfide Cross-Linked Corona and Polyester Core Domains
Paclitaxel-loaded
shell cross-linked polymeric nanoparticles
having an enzymatically and hydrolytically degradable poly(lactic
acid) core and a glutathione-responsive disulfide cross-linked poly(oligoethylene
glycol)-containing corona were constructed in aqueous solution and
investigated for their stimuli-responsive release of the embedded
therapeutics and <i>in vitro</i> cytotoxicity. Paclitaxel
release from the nanoparticles in PBS buffer was accelerated in the
presence of glutathione at both pH 5.5 and pH 7.4, reaching <i>ca</i>. 65% cumulative drug release after 8 d, whereas only <i>ca</i>. 50% and 35% extents of release were observed in the
absence of glutathione at pH 5.5 and pH 7.4, respectively. Enzyme-catalyzed
hydrolysis of the nanoparticle core resulted in the degradation of <i>ca</i>. 30% of the poly(lactic acid) core to lactic acid within
12 h, with coincidently triggered paclitaxel release of <i>ca</i>. 37%, as opposed to only <i>ca</i>. 17% release from the
uncatalyzed nanoparticles at pH 7.4. While empty nanoparticles did
not show any inherent cytotoxicity at the highest tested concentrations,
paclitaxel-loaded nanoparticles showed IC<sub>50</sub> values that
were similar to those of free paclitaxel at 72 h incubation with KB
cells and were more efficacious at <i>ca</i>. 3-fold lower
IC<sub>50</sub> value (0.031 μM vs 0.085 μM) at 2 h of
incubation. Against human ovarian adenocarcinoma cells, the paclitaxel-loaded
nanoparticles exhibited a remarkable <i>ca</i>. 11-fold
lower IC<sub>50</sub> than a Taxol-mimicking formulation (0.0007 μM
vs 0.008 μM) at 72 h of incubation. These tunable dual-responsive
degradable nanoparticles show great promise for delivery of paclitaxel
to tumor tissues, given their superior <i>in vitro</i> efficacies
compared to that of free paclitaxel and Taxol-mimicking formulations
<i>In Vitro</i> Efficacy of Paclitaxel-Loaded Dual-Responsive Shell Cross-Linked Polymer Nanoparticles Having Orthogonally Degradable Disulfide Cross-Linked Corona and Polyester Core Domains
Paclitaxel-loaded
shell cross-linked polymeric nanoparticles
having an enzymatically and hydrolytically degradable poly(lactic
acid) core and a glutathione-responsive disulfide cross-linked poly(oligoethylene
glycol)-containing corona were constructed in aqueous solution and
investigated for their stimuli-responsive release of the embedded
therapeutics and <i>in vitro</i> cytotoxicity. Paclitaxel
release from the nanoparticles in PBS buffer was accelerated in the
presence of glutathione at both pH 5.5 and pH 7.4, reaching <i>ca</i>. 65% cumulative drug release after 8 d, whereas only <i>ca</i>. 50% and 35% extents of release were observed in the
absence of glutathione at pH 5.5 and pH 7.4, respectively. Enzyme-catalyzed
hydrolysis of the nanoparticle core resulted in the degradation of <i>ca</i>. 30% of the poly(lactic acid) core to lactic acid within
12 h, with coincidently triggered paclitaxel release of <i>ca</i>. 37%, as opposed to only <i>ca</i>. 17% release from the
uncatalyzed nanoparticles at pH 7.4. While empty nanoparticles did
not show any inherent cytotoxicity at the highest tested concentrations,
paclitaxel-loaded nanoparticles showed IC<sub>50</sub> values that
were similar to those of free paclitaxel at 72 h incubation with KB
cells and were more efficacious at <i>ca</i>. 3-fold lower
IC<sub>50</sub> value (0.031 μM vs 0.085 μM) at 2 h of
incubation. Against human ovarian adenocarcinoma cells, the paclitaxel-loaded
nanoparticles exhibited a remarkable <i>ca</i>. 11-fold
lower IC<sub>50</sub> than a Taxol-mimicking formulation (0.0007 μM
vs 0.008 μM) at 72 h of incubation. These tunable dual-responsive
degradable nanoparticles show great promise for delivery of paclitaxel
to tumor tissues, given their superior <i>in vitro</i> efficacies
compared to that of free paclitaxel and Taxol-mimicking formulations
Health status after invasive or conservative care in coronary and advanced kidney disease
BACKGROUND In the ISCHEMIA-CKD trial, the primary analysis showed no significant difference in the risk of death or myocardial infarction with initial angiography and revascularization plus guideline-based medical therapy (invasive strategy) as compared with guideline-based medical therapy alone (conservative strategy) in participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease (an estimated glomerular filtration rate of <30 ml per minute per 1.73 m2 or receipt of dialysis). A secondary objective of the trial was to assess angina-related health status. METHODS We assessed health status with the Seattle Angina Questionnaire (SAQ) before randomization and at 1.5, 3, and 6 months and every 6 months thereafter. The primary outcome of this analysis was the SAQ Summary score (ranging from 0 to 100, with higher scores indicating less frequent angina and better function and quality of life). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate the treatment effect with the invasive strategy. RESULTS Health status was assessed in 705 of 777 participants. Nearly half the participants (49%) had had no angina during the month before randomization. At 3 months, the estimated mean difference between the invasive-strategy group and the conservative-strategy group in the SAQ Summary score was 2.1 points (95% credible interval, 120.4 to 4.6), a result that favored the invasive strategy. The mean difference in score at 3 months was largest among participants with daily or weekly angina at baseline (10.1 points; 95% credible interval, 0.0 to 19.9), smaller among those with monthly angina at baseline (2.2 points; 95% credible interval, 122.0 to 6.2), and nearly absent among those without angina at baseline (0.6 points; 95% credible interval, 121.9 to 3.3). By 6 months, the between-group difference in the overall trial population was attenuated (0.5 points; 95% credible interval, 122.2 to 3.4). CONCLUSIONS Participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease did not have substantial or sustained benefits with regard to angina-related health status with an initially invasive strategy as compared with a conservative strategy
Management of coronary disease in patients with advanced kidney disease
BACKGROUND Clinical trials that have assessed the effect of revascularization in patients with stable coronary disease have routinely excluded those with advanced chronic kidney disease. METHODS We randomly assigned 777 patients with advanced kidney disease and moderate or severe ischemia on stress testing to be treated with an initial invasive strategy consisting of coronary angiography and revascularization (if appropriate) added to medical therapy or an initial conservative strategy consisting of medical therapy alone and angiography reserved for those in whom medical therapy had failed. The primary outcome was a composite of death or nonfatal myocardial infarction. A key secondary outcome was a composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. RESULTS At a median follow-up of 2.2 years, a primary outcome event had occurred in 123 patients in the invasive-strategy group and in 129 patients in the conservative-strategy group (estimated 3-year event rate, 36.4% vs. 36.7%; adjusted hazard ratio, 1.01; 95% confidence interval [CI], 0.79 to 1.29; P=0.95). Results for the key secondary outcome were similar (38.5% vs. 39.7%; hazard ratio, 1.01; 95% CI, 0.79 to 1.29). The invasive strategy was associated with a higher incidence of stroke than the conservative strategy (hazard ratio, 3.76; 95% CI, 1.52 to 9.32; P=0.004) and with a higher incidence of death or initiation of dialysis (hazard ratio, 1.48; 95% CI, 1.04 to 2.11; P=0.03). CONCLUSIONS Among patients with stable coronary disease, advanced chronic kidney disease, and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of death or nonfatal myocardial infarction