Polymeric nanocapsules comprised of hydrophobic shells and hollow aqueous interiors are an extremely useful class of nanomaterial, particularly in the encapsulation and controlled delivery of hydrophilic cargo. Generally prepared via droplet or latex templation approaches, polymeric nanocapsules are mostly spherical. Controlling the morphology of hollow nanocapsules is an intriguing design challenge. Non-spherical, or elongated, templates are often inorganic materials which do not directly impart a hollow interior, and their post-polymerization removal is not straightforward. This study outlines a novel strategy for the preparation of elongated nanocapsules, wherein elongated liposomes are deployed as hollow templates. Initially, ciprofloxacin drug nanocrystals were utilized to facilitate the formation of elongated liposomes, followed by adsorption of reversible addition-fragmentation chain transfer (RAFT) oligomers. Subsequent chain-extension polymerization furnished the desired elongated nanocapsule morphology. This proof-of-concept study contributes towards the goal of elongated nanocapsule synthesis, a morphology which can impart improved circulation times in the field of drug delivery.

In this study, the effect of the polymer structural difference introduced by radical ring-opening polymerization (rROP) of a cyclic ketene acetal (CKA) monomer, analogous to epsilon-caprolactone (CL), on the nanoencapsulation and controlled release of hydrophobic actives curcumin and fenofibrate was explored. The two chosen polymers are amphiphilic diblock copolymers namely methoxy poly(ethylene glycol)- b -poly( epsilon-caprolactone) (mPEG- b - PCL) and methoxy poly(ethylene glycol)- b -poly(2-methylene-1,3-dioxepane) (mPEG- b -PMDO). Both polymers serve as a good comparison as they have a similar average molecular weight ( M n ) and the same hydrophilic PEG chains with the main difference in microstructure of hydrophobic PCL and PMDO chains. Nuclear magnetic resonance spectroscopy (NMR) ( 1 H and 13 C), gel permeation chromatography (GPC), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray diffraction (X -RD) confirmed the structures of the polymers. mPEG- b -PMDO possesses less crystallinity or is more amorphous as compared to the linear mPEG- b - PCL due to branching or polymer disorder in the hydrophobic segment as a result of radical mechanism operating in rROP. The subsequent nanoencapsulation of hydrophobic active curcumin with mPEG- b -PMDO yielded higher loading content (LC) and encapsulation efficiency (EE) in the hydrophobic core of the nanoparticle (NP) due to more hydrophobic interactions between hydrophobic core and hydrophobic active. In contrast, lower LC and EE were observed for the nanoencapsulation of fenofibrate with mPEG- b -PMDO. The further release experiments were carried out in the aqueous and hydro-alcoholic systems over a period of 24 h at 37 degrees C. These experiments further supported our hypothesis regarding the influence of polymer structure, revealing slower, controlled, and more consistent release profiles for both curcumin and fenofibrate with mPEG- b -PMDO compared to mPEG- b - PCL. Our approach could open new opportunities for utilizing this polymer in personal care and biomedical applications.

Polymeric nanocapsules have been studied as drug delivery carriers for a great variety of drugs for more than 30 years. In particular, nonspherical polymeric nanoparticles with solid cores are highlighted for their capability to influence cellular uptake and circulation time in the bloodstream. However, the promising combination of nonspherical morphology and the existence of an internal cavity to encapsulate a high dose of pharmaceutical actives has not yet been fully achieved. This review systematically addresses the development of nonspherical nanocapsules with a cross-linked shell or self-assembled membrane (polymersomes). Ellipsoidal, tetrahedral, cubic, protrusion-shaped, dumbbell-shaped, and snowman-shaped nanocapsules are discussed. The relationship between the formed morphologies and the use of different templates, monomers, or methods of polymerization are elucidated for future design of more functional shapes.

Degradable poly(acrylic acid) has been prepared via free radical ring-opening copolymerization of tert-butyl acrylate and 2-methylene-1,3-dioxepane followed by tert-butyl deprotection, under acidic conditions. The resulting degradable poly(acrylic acid) analogue possesses ester groups within the backbone, which facilitate environmental hydrolysis into short chain oligomers, which subsequently undergo biodegradation. The degradable poly(acrylic acid) reported displays a significant degree of biodegradability (27.50% in 28 days) under environmental conditions, when compared to a conventional all carbon backbone non-degradable version, which shows no biodegradability.

Antagonists of the P2X7 receptor (P2X7R) have the potential to treat diseases where neuroinflammation is present such as depression, chronic pain and Alzheimer's disease. We recently developed a structural hybrid (C1; 1-((adamantan-1-yemethyl)-2-cyano-3-(quinolin-5-yeguanidine) of a purported competitive P2X7R antagonist (C2; 2-cyano-1-((1S)-1-phenylethyl)-3-(quinolin-5-yl)guanidine) and a likely negative allosteric modulator (NAM) of the P2X7R (C3; N-((adamantan-1-yl)methyl)-2-chloro-5-methoxybenzamide). Here we aimed to pharmacologically characterize C1, to gain insights into how select structural components impact antagonist interaction with the P2X7R. A second aim was to examine the role of the peptide LL-37, an apparent activator of the P2X7R, and compare the ability of multiple P2X7R antagonists to block its effects. Compounds 1, 2 and 3 were characterised using washout, Schild and receptor protection studies, all using dye uptake assays in HEK293 cells expressing the P2X7R. LL-37 was examined in the same HEK293 cells and THP-1 monocytes. Compounds 2 and 3 acted as a BzATP-competitive antagonist and NAM of the P2X7R respectively. Compound 1 was a slowly reversible NAM of the P2X7R suggesting the incorporation of an appropriately positioned adamantane promotes binding to the allosteric site of the P2X7R. LL-37 was shown to potentiate the ability of ATP to induce dye uptake at low concentrations (1-3 mu g mL(-1)) or induce dye uptake alone at higher concentrations (10-20 mu g mL(-1)). None of the P2X7R antagonists studied were able to block LL-37-induced dye uptake bringing in to question the ability of current P2X7R antagonists to inhibit the inflammatory action of LL-37 in vivo.

Environmental accumulation of non-degradable polystyrene (PS) microparticles from plastic waste poses potential adverse impact on marine life and human health. Herein, microparticles from a degradable PS analogue (dePS) are formulated and their immuno-modulatory characteristics are comprehensively evaluated. Both dePS copolymer and microparticles are chemically degradable under accelerated hydrolytic condition. In vitro studies show that dePS microparticles are non-toxic to three immortalized cell lines. While dePS microparticles do not induce macrophage polarization in vitro, dePS microparticles induce in vivo upregulation of both pro-inflammatory and anti-inflammatory biomarkers in immuno-competent mice, suggesting the coexistence of mixed phenotypes of macrophages in the host immune response to these microparticles. Interestingly, on day 7 following subcutaneous in mice, dePS microparticles induce a lower level of several immuno-modulatory biomarkers (matrix metallo-proteinases (MMPs), tumor necrosis factor (TNF-α), and arginase activity) compared to that of reference poly(lactic-co-glycolic acid) microparticles. Remarkably, compared to PS microparticles, dePS microparticles exhibit similar in vitro and in vivo bioactivity while acquiring additional chemical degradability. Overall, this study gains new insights into the host immune response to dePS microparticles and suggests that this dePS analogue might be explored as an alternative material choice for biomedical and consumer care applications.

Introduction: Prenatal ethanol exposure (PEE) has been shown to alter the level and function of receptors in the brain, one of which is GABA(a) receptors (GABA(a)R), the major inhibitory ligand gated ion channels that mediate neuronal inhibition. High dose PEE in animals resulted in the upregulation of GABA(a)R, but the effects of low and moderate dose PEE at early gestation have not been investigated. This study aimed at examining GABA(a)R density in the adult mouse brain following PEE during a period equivalent to the first 3 to 4 weeks in human gestation. It was hypothesized that early moderate PEE would cause alterations in brain GABA(a)R levels in the adult offspring. Methods: C57BL/6J mice were given 10% v/v ethanol during the first 8 gestational days. Male offspring were studied using in-vivo Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI), biodistribution, invitro autoradiography using [F-18]AH114726. a novel flumazenil analogue with a high affinity for the benzodiazepine-binding site, and validated using immunohistochemistry. Results: In vivo PET and biodistribution did not detect alteration in brain tracer uptake. In vitro radiotracer studies detected significantly reduced GABA(a)R in the olfactory bulbs. Immunohistochemistry detected reduced GABA(a)R in the cerebral cortex, cerebellum and hippocampus, while Nissl staining showed that cell density was significantly higher in the striatum following PEE. Conclusion: Early moderate PEE may induce long-term alterations in the GABA(a)R system that persisted into adulthood. (C) 2020 Elsevier Inc. All rights reserved.

Monoamine oxidase B (MAO-B) is an important enzyme regulating the levels of monoaminergic neurotransmitters. Selective MAO-B inhibitors have been labeled with carbon-11 or fluorine-18 to visualize the localization of MAO-B in vivo by positron emission tomography (PET) and thereby have been useful for studying neurodegenerative diseases. The aim of this study was to develop promising fluorine-18 labeled reversible MAO-B PET radioligands and their biological evaluation in vitro by autoradiography. Radiolabeling was achieved by classical one-step fluorine-18 nucleophilic substitution reaction. The stability and radiochemical yield was analyzed with HPLC. All five fluorine-18 labeled compounds were tested in human whole hemisphere autoradiography experiments. Five compounds (GEH200439, GEH200448, GEH200449, GEH200431A, and GEH200431B) were successfully radiolabeled with fluorine-18, and the incorporation yield of the fluorination reactions varied from 10 to 45% depending on the compound. The radiochemical purity was higher than 99% for all at the end of synthesis. Radioligands were found to be stable, with a radiochemical purity of >99% in a sterile phosphate buffered saline (pH = 7.4) over the duration of the study. The ARG binding density of only 18F-GEH200449 was consistent with known MAO-B expression in the human brain. Radiolabeling of five new fluorine-18 MAO-B reversible inhibitors was successfully accomplished. Compound 18F-GEH200449 binds specifically to MAO-B in vitro postmortem brain and could be a potential candidate for in vivo PET investigation.

Biocompatible nano-capsules (polymer vesicles) were prepared by combining NaI-catalyzed living radical polymerization with aqueous emulsion PISA (polymerization induced self-assembly). Poly(ethylene glycol) methyl ether methacrylate (PEGMA) and methyl methacrylate (MMA) were used as hydrophilic and hydrophobic monomers, respectively. Spheres and vesicles were generated depending on the degrees of polymerization of the hydrophilic and hydrophobic segments in the block copolymers. The spheres and vesicles were crosslinked using a divinyl monomer (ethylene glycol dimethacrylate (EGDMA)) as a co-monomer of MMAin situduring the polymerization. The encapsulation ability of the obtained vesicle was studied using a hydrophilic dye,i.e., rhodamine-B.

Radical ring-opening copolymerization (rROP) between 2-methylene-1,3-dioxepane (MDO) and methacrylic acid N-hydroxysuccinimide ester (NHSMA) furnishes a reactive polyester-based linear copolymer precursor. Subsequent cross-linker mediated chain collapse affords degradable single-chain nanoparticles (DSCNPs). This methodology is an experimentally robust and straightforward route to main-chain degradable polymeric nanoparticles in the sub-30 nm size range.

Degradable analogues of polystyrene are synthesized via radical ring-opening (co)polymerization (rROP) between styrene and two cyclic ketene acetals, namely 2-methylene-1,3-dioxepane (MDO) and 5,6-benzo-2-methylene-1,3-dioxepane (BMDO). This approach periodically inserts ester bonds throughout the main chain of polystyrene, imparting a degradation pathway via ester hydrolysis. We discuss the historical record of this approach, with careful attention paid to the conflicting findings previously reported. We have found a common 1H NMR characterization error, repeated throughout the existing body of work. This misinterpretation is responsible for the discrepancies within the cyclic ketene acetal (CKA)-based degradable polystyrene literature. These inconsistencies, for the first time, are now understood and resolved through optimization of the polymerization conditions, and detailed characterization of the degradable copolymers and their corresponding oligomers after hydrolytic degradation.

Noninvasive bioimaging techniques are critical for assessing the biodistribution of cellular therapies longitudinally. Among them, photoacoustic imaging (PAI) can generate high-resolution images with a tissue penetration depth of ∼4 cm. However, it is essential and still highly challenging to develop stable and efficient near-infrared (NIR) probes with low toxicity for PAI. We report here the preparation and use of perylene diimide derivative (PDI) with NIR absorbance (around 700 nm) as nanoprobes for tracking mesenchymal stromal cells (MSCs) in mice. Employing an in-house synthesized star hyperbranched polymer as a stabilizer is the key to the formation of stable PDI nanoparticles with low toxicity and high uptake by the MSCs. The PDI nanoparticles remain within the MSCs as demonstrated by in vitro and in vivo assessments. The PDI-labeled MSCs injected subcutaneously on the flanks of the mice are clearly visualized with PAI up to 11 days postadministration. Furthermore, bioluminescence imaging of PDI-labeled luciferase-expressing MSCs confirms that the administered cells remain viable for the duration of the experiment. These PDI nanoprobes thus have good potential for tracking administered cells in vivo using PAI.

While synthetic polymers have found widespread application in personal and consumer care, and agrochemical and biomedical applications, there remains a constant drive to increase the level of sophistication within polymeric systems to further improve their utility. Dating back to 1993, reversible-deactivation radical polymerization (RDRP) techniques have been commonly adopted to increase complexity. In the intervening 27 years we have seen tremendous progress in the preparation of remarkable polymeric architectures, possessing exotic morphologies, stimuliresponsiveness and diverse functionality. However, their post-use accumulation in the natural world and human body is a topic of growing concern. Therefore, the development of degradable polymeric structures is an important objective facing polymer chemists. Imparting degradability, in the form of main-chain ester bonds, into free radical chain-growth polymers can be achieved via radical ring-opening polymerization (rROP) of cyclic ketene acetals (CKAs) in the presence of conventional vinyl monomers. While this method has been well understood since 1982, more recent efforts have pursued the incorporation of CKA monomers within a wider range of polymeric materials. This review discusses the exciting progress made combining RDRP techniques with rROP of CKAs. Research at the interface of these two fields presents an extremely attractive route towards degradable complex polymeric architectures.

Poly(alkyl)acrylates are a major class of nonbiodegradable polymers which are difficult to recycle due to an all-carbon backbone. Introducing a certain number of ester bonds in the backbone via radical ring opening copolymerization of acrylates with 2-methylene-1,3 dioxepane (MDO) improves its degradability and may be promising for chemical recycling. The current work examines the influence of monomer addition profiles on the copolymerization of acrylates with MDO. We improved the homogeneity of the MDO insertion through a semibatch approach, which was demonstrated by the molecular weight distribution of fragments after alkali degradation. By detailed NMR analysis, we identified the incorporation of MDO ring retained units, formation of branches on acrylate units, and formation of branches on MDO ring open units as the key side reactions. Theoretical calculations showed that mainly kinetic factors influence the outcome of the polymerization.

Stimuli-responsive polymeric nanoparticles are very attractive materials often developed for the uptake and controlled release of active molecules, especially in personal and consumer care, agriculture and biomedical applications. However, a significant challenge for polymer scientists is the incorporation of specific functionality and stimuli-responsiveness, while simultaneously including a degradability mechanism to prevent undesirable build-up of the nanoparticle after its specific function is complete. We report, a straightforward synthetic strategy for the preparation of pH-responsive and covalently cross-linked polymeric nanoparticles possessing degradable ester-links in the main-chain of their linear polymer building blocks. This is achieved by combining reversible-addition fragmentation chain-transfer (RAFT) polymerization of conventional vinyl monomers with radical ring-opening polymerization of a cyclic ketene acetal monomer. A PEGylated macro-RAFT chain transfer agent facilitates the radical copolymerization of 2-(diethylamino)ethyl methacrylate, N-hydroxysuccinimide ester methacrylic acid and 2-methylene-1,3-dioxepane affording stimuli-responsive and activated ester functional copolymers which possess ester bonds periodically within their main-chain. These polymers undergo pH-triggered self-assembly. Subsequent, nanoparticle covalent cross-linked is achieved via amide bond formation, while maintaining a degradability mechanism through hydrolysis of the main-chain ester bonds.

Vesicle templated emulsion polymerization is a special form of emulsion polymerization where the polymer is grown from the outside of the vesicle, leading to nanocapsules. Cost effective nanocapsules synthesis is in high demand due to phasing out of older methods for capsule synthesis. Although the first indications of this route being successful were published some 10 years ago, until now a thorough understanding of the parameters controlling the morphologies resulting from the template emulsion polymerization was lacking. Most often a mixture of different morphologies was obtained, ranging from solid particles to pro-trusion structures to nanocapsules. A high yield of nanocapsules was not achieved until now. In this paper, the influence of initial vesicle dispersion, choice of the Reversible Addition-Fragmentation chain Transfer (RAFT) species and oligomer, monomer and crosslinker have been investigated. It turns out that good initial vesicle dispersion, molecular control of the RAFT process, a not too hydrophobic monomer and some crosslinking is needed to result in high yield of nanocapsules. In previous work, the level of RAFT control was often suboptimal and not properly verified and although nanocapsules were shown, other morphologies were also present. We now believe we have a full understanding of vesicle templated nanocapsules synthesis, relevant to many applications.

Low water solubility and poor bioavailability of hydrophobic pharmaceuticals are significant problems in drug formulation. This research presents a bottom-up route to prepare nanoparticles of hydrophobic actives which is synthetically straightforward, robust, and can be applied to a range of active molecules. A series of amphiphilic branched diblock copolymers have been prepared via the conventional radical polymerization of a vinyl monomer (styrene, butylmethacrylate, or N-isopropylacrylamide) and a corresponding divinyl cross-linker facilitated by a poly(ethylene glycol)-based macro-initiator. These materials were employed as stabilizers in the emulsion-freeze-drying methodology to prepare nanoparticles of hydrophobic pharmaceuticals. It is demonstrated that these branched diblock copolymers are able to facilitate the formation of Triclosan nanoparticles which display enhanced antimicrobial activity against Candida albicans, when compared to non-processed (used as received) Triclosan. This process requires significantly lower levels of stabilizer compared to previously reported surfactant/polymer systems after optimization of polymer properties and morphology.