Biodegradable PEG-poly(ω-pentadecalactone- co - p -dioxanone) nanoparticles for enhanced and sustained drug delivery to treat brain tumors

Intracranial delivery of therapeutic agents is limited by penetration beyond the blood-brain barrier (BBB) and rapid metabolism of the drugs that are delivered. Convection-enhanced delivery (CED) of drugloaded nanoparticles (NPs) provides for local administration, control of distribution, and sustained drug release. While some investigators have shown that repeated CED procedures are possible, longer periods of sustained release could eliminate the need for repeated infusions, which would enhance safety and translatability of the approach. Here, we demonstrate that nanoparticles formed from poly(ethylene glycol)-poly(u-pentadecalactone-co-p-dioxanone) block copolymers [PEG-poly(PDL-co- DO)] are highly efficient nanocarriers that provide long-term release: small nanoparticles (less than 100 nm in diameter) continuously released a radiosensitizer (VE822) over a period of several weeks in vitro, provided widespread intracranial drug distribution during CED, and yielded significant drug retention within the brain for over 1 week. One advantage of PEG-poly(PDL-co-DO) nanoparticles is that hydrophobicity can be tuned by adjusting the ratio of hydrophobic PDL to hydrophilic DO monomers, thus making it possible to achieve a wide range of drug release rates and drug distribution profiles. When administered by CED to rats with intracranial RG2 tumors, and combined with a 5-day course of fractionated radiation therapy, VE822-loaded PEG-poly(PDL-co-DO) NPs significantly prolonged survival when compared to free VE822. Thus, PEG-poly(PDL-co-DO) NPs represent a new type of versatile nanocarrier system with potential for sustained intracranial delivery of therapeutic agents to treat brain tumors

The Effect by Lucy Prebble: A Theater Comps Production by Will Josowitz

THE EFFECT by Lucy Prebble When Connie and Tristan first meet on a clinical drug-trial for antidepressants, their flirtation with each other seems fun and exciting. However as the trial progresses, they begin to question whether they\u27re truly infatuated or simply under the effects of medication. This 1 hour 40 minute play explores love and mortality all while raising a critical eye to the origin of the drugs we choose to medicate ourselves with

Human Engineered Cardiac Tissues Created Using Induced Pluripotent Stem Cells Reveal Functional Characteristics of BRAF-Mediated Hypertrophic Cardiomyopathy

<div><p>Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death that often goes undetected in the general population. HCM is also prevalent in patients with cardio-facio-cutaneous syndrome (CFCS), which is a genetic disorder characterized by aberrant signaling in the RAS/MAPK signaling cascade. Understanding the mechanisms of HCM development in such RASopathies may lead to novel therapeutic strategies, but relevant experimental models of the human condition are lacking. Therefore, the objective of this study was to develop the first 3D human engineered cardiac tissue (hECT) model of HCM. The hECTs were created using human cardiomyocytes obtained by directed differentiation of induced pluripotent stem cells derived from a patient with CFCS due to an activating BRAF mutation. The mutant myocytes were directly conjugated at a 3:1 ratio with a stromal cell population to create a tissue of defined composition. Compared to healthy patient control hECTs, BRAF-hECTs displayed a hypertrophic phenotype by culture day 6, with significantly increased tissue size, twitch force, and atrial natriuretic peptide (ANP) gene expression. Twitch characteristics reflected increased contraction and relaxation rates and shorter twitch duration in BRAF-hECTs, which also had a significantly higher maximum capture rate and lower excitation threshold during electrical pacing, consistent with a more arrhythmogenic substrate. By culture day 11, twitch force was no longer different between BRAF and wild-type hECTs, revealing a temporal aspect of disease modeling with tissue engineering. Principal component analysis identified diastolic force as a key factor that changed from day 6 to day 11, supported by a higher passive stiffness in day 11 BRAF-hECTs. In summary, human engineered cardiac tissues created from BRAF mutant cells recapitulated, for the first time, key aspects of the HCM phenotype, offering a new <i>in vitro</i> model for studying intrinsic mechanisms and screening new therapeutic approaches for this lethal form of heart disease.</p></div

Twitch force characteristics of wild-type and BRAF-mutant hECTs.

<p>(<b>A</b>) Cartoon of iPSC-derived hECT force data illustrating twitch characteristic parameters. (<b>B-G</b>) Mean (±SD) twitch parameters for wild-type (open bars, n = 7) and BRAF mutant (solid bars, n = 5) iPSC-hECTs tested on culture days 6 and 11, including developed force (<b>B</b>), 50% twitch duration (<b>C</b>), time to 50% contraction (<b>D</b>), time to 50% relaxation (<b>E</b>) and the maximum rates of contraction (<b>F</b>) and relaxation (<b>G</b>). * p < 0.05, ** p < 0.01, *** p < 0.001.</p