In vivo clearance of 19F MRI imaging nanocarriers is strongly influenced by nanoparticle ultrastructure

Perfluorocarbons hold great promise both as imaging agents, particularly for (19)F MRI, and in therapy, such as oxygen delivery. (19)F MRI is unique in its ability to unambiguously track and quantify a tracer while maintaining anatomic context, and without the use of ionizing radiation. This is particularly well-suited for inflammation imaging and quantitative cell tracking. However, perfluorocarbons, which are best suited for imaging - like perfluoro-15-crown-5 ether (PFCE) - tend to have extremely long biological retention. Here, we showed that the use of a multi-core PLGA nanoparticle entrapping PFCE allows for a 15-fold reduction of half-life in vivo compared to what is reported in literature. This unexpected rapid decrease in (19)F signal was observed in liver, spleen and within the infarcted region after myocardial infarction and was confirmed by whole body NMR spectroscopy. We demonstrate that the fast clearance is due to disassembly of the ~200 nm nanoparticle into ~30 nm domains that remain soluble and are cleared quickly. We show here that the nanoparticle ultrastructure has a direct impact on in vivo clearance of its cargo i.e. allowing fast release of PFCE, and therefore also bringing the possibility of multifunctional nanoparticle-based imaging to translational imaging, therapy and diagnostics

Mechanical methods for induction of labour

Background Mechanical methods were the first methods developed to ripen the cervix and induce labour.During recent decades they have been substituted by pharmacological methods. Potential advantages of mechanical methods, compared with pharmacological methods may include reduction in side effects that could improve neonatal outcomes. This is an update of a review first published in 2001, last updated in 2012. Objectives To determine the effectiveness and safety of mechanical methods for third trimester (> 24 weeks' gestation) induction of labour in comparison with prostaglandin E2 (PGE2) (vaginal and intracervical), low-dose misoprostol (oral and vaginal), amniotomy or oxytocin. Search methods For this update, we searched Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies (9 January 2018). We updated the search in March 2019 and added the search results to the awaiting classification section of the review. Selection criteria Clinicaltrials comparingmechanicalmethodsusedforthirdtrimester cervicalripeningorlabourinductionwithpharmacologicalmethods. Mechanical methods include: (1) the introduction of a catheter through the cervix into the extra-amniotic space with balloon insufflation; (2) introduction of laminaria tents, or their synthetic equivalent (Dilapan), into the cervical canal; (3) use of a catheter to inject fluid into the extra-amniotic space (EASI). This review includes the following comparisons: (1) specific mechanical methods (balloon catheter, laminaria tents or EASI) compared with prostaglandins (different types, different routes) or with oxytocin; (2) single balloon compared to a double balloon; (3) addition of prostaglandins or oxytocin to mechanical methods compared with prostaglandins or oxytocin alone. Data collection and analysis Two review authors independently assessed trials for inclusion and assessed risk of bias. Two review authors independently extracted data and assessed the quality of the evidence using the GRADE approach. Main results This review update includes a total of 113 trials (22,373 women) contributing data to 21 comparisons. Risk of bias of trials varied. Overall, the evidence was graded from very-low to moderate quality. All evidence was downgraded f

Biodegradable polyphosphoester micelles act as both background-free 31P magnetic resonance imaging agents and drug nanocarriers

Abstract In vivo monitoring of polymers is crucial for drug delivery and tissue regeneration. Magnetic resonance imaging (MRI) is a whole-body imaging technique, and heteronuclear MRI allows quantitative imaging. However, MRI agents can result in environmental pollution and organ accumulation. To address this, we introduce biocompatible and biodegradable polyphosphoesters, as MRI-traceable polymers using the 31P centers in the polymer backbone. We overcome challenges in 31P MRI, including background interference and low sensitivity, by modifying the molecular environment of 31P, assembling polymers into colloids, and tailoring the polymers’ microstructure to adjust MRI-relaxation times. Specifically, gradient-type polyphosphonate-copolymers demonstrate improved MRI-relaxation times compared to homo- and block copolymers, making them suitable for imaging. We validate background-free imaging and biodegradation in vivo using Manduca sexta. Furthermore, encapsulating the potent drug PROTAC allows using these amphiphilic copolymers to simultaneously deliver drugs, enabling theranostics. This first report paves the way for polyphosphoesters as background-free MRI-traceable polymers for theranostic applications

Biodegradable Polyphosphoester Micelles Act as Both Background-free 31P Magnetic Resonance Imaging Agents and Drug Nanocarriers

Imaging and tracing materials inside the body is essential to develop functional materials for personalized therapies, including drug delivering nanocarriers and artificial tissues. Magnetic Resonance Imaging (MRI) is a key whole-body imaging technology, where heteronuclear MRI agents enable background-free, quantitative labeling. However, many MRI agents raised concerns due to environmental pollution and organ accumulation. As a solution, we developed a biodegradable, biocompatible polymer platform for heteronuclear 31P magnetic resonance imaging (MRI). We introduce polyphosphoester colloids for heteronuclear MRI using 31P-nucleus. 31P MRI has been severely hampered by unfavorable magnetic resonance properties of 31P, including intrinsic background and low sensitivity. We overcame these fundamental challenges in imaging of 31P by tailoring molecular and structural features of polymeric colloids. We have synthesized gradient-type polyphosphonate copolymers that self-assemble into well-defined micelles. The gradient leads to favorable MRI characteristics compared with homo- and block copolymers. Background-free imaging and biodegradation were proven in vivo in Manduca sexta. Furthermore, we demonstrate by encapsulation of the potent drug PROTAC ARV-825 that these amphiphilic copolymers can simultaneously deliver hydrophobic drugs and thus enable theranostics. We present a unique platform of biocompatible, degradable polyphosphoesters that inherently act as background-free MRI agents and delivery vehicles