74 research outputs found
Influence of block versus random monomer distribution on the cellular uptake of hydrophilic copolymers
The use of polymers has revolutionized the field of drug delivery in the past two decades. Properties such as polymer size, charge, hydrophilicity, or branching have all been shown to play an important role in the cellular internalization of polymeric systems. In contrast, the fundamental impact of monomer distribution on the resulting biological properties of copolymers remains poorly studied and is always only investigated for biologically active self-assembling polymeric systems. Here, we explore the fundamental influence of monomer distribution on the cellular uptake of nonaggregating and biologically passive copolymers. Reversible addition–fragmentation chain-transfer (RAFT) polymerization was used to prepare precisely defined copolymers of three hydrophilic acrylamide monomers. The cellular internalization of block copolymers was compared with the uptake of a random copolymer where monomers are statistically distributed along the chain. The results demonstrate that monomer distribution in itself has a negligible impact on copolymer uptake
One-pot RAFT and fast polymersomes assembly: a ‘beeline’ from monomers to drug-loaded nanovectors
Rapid and simple routes to functional polymersomes are increasingly needed to expand their clinical or industrial applications. Here we describe a novel strategy where polymersomes are prepared through an in-line process in just a few hours, starting from simple acrylate or acrylamide monomers. Using Perrier's protocol, well-defined amphiphilic diblock copolymers formed from PEG acrylate (mPEGA480), 2-(acryloyloxy)ethyl-3-chloro-4-hydroxybenzoate (ACH) or 2-(3-chloro-4-hydroxybenzamido)ethyl acrylate (CHB), have been synthesised by RAFT polymerisation in one-pot, pushing the monomer conversion for each block close to completion (≥94%). The reaction mixture, consisting of green biocompatible solvents (ethanol/water) have then been directly utilised to generate well-defined polymersomes, by simple cannulation into water or in a more automated process, by using a bespoke microfluidic device. Terbinafine and cyanocobalamine were used to demonstrate the suitability of the process to incorporate model hydrophobic and hydrophilic drugs, respectively. Vesicles size and morphology were characterised by DLS, TEM, and AFM. In this work we show that materials and experimental conditions can be chosen to allow facile and rapid generation drug-loaded polymersomes, through a suitable in-line process, directly from acrylate or acrylamide monomer building blocks
Stunted children display ectopic small intestinal colonization by oral bacteria, which cause lipid malabsorption in experimental models
Environmental enteric dysfunction (EED) is an inflammatory syndrome postulated to contribute to stunted child growth and to be associated with intestinal dysbiosis and nutrient malabsorption. However, the small intestinal contributions to EED remain poorly understood. This study aimed to assess changes in the proximal and distal intestinal microbiota in the context of stunting and EED and to test for a causal role of these bacterial isolates in the underlying pathophysiology. We performed a cross-sectional study in two African countries recruiting roughly 1,000 children aged 2 to 5 years and assessed the microbiota in the stomach, duodenum, and feces. Upper gastrointestinal samples were obtained from stunted children and stratified according to stunting severity. Fecal samples were collected. We then investigated the role of clinical isolates in EED pathophysiology using tissue culture and animal models. We find that small intestinal bacterial overgrowth (SIBO) is extremely common (>80%) in stunted children. SIBO is frequently characterized by an overgrowth of oral bacteria, leading to increased permeability and inflammation and to replacement of classical small intestinal strains. These duodenal bacterial isolates decrease lipid absorption in both cultured enterocytes and mice, providing a mechanism by which they may exacerbate EED and stunting. Further, we find a specific fecal signature associated with the EED markers fecal calprotectin and alpha-antitrypsin. Our study shows a causal implication of ectopic colonization of oral bacterial isolated from the small intestine in nutrient malabsorption and gut leakiness in vitro. These findings have important therapeutic implications for modulating the microbiota through microbiota-targeted interventions
Preparation of Inert Polystyrene Latex Particles as MicroRNA Delivery Vectors by Surfactant-Free RAFT Emulsion Polymerization
Post-assembly modification of kinetically metastable Fe(II)2L3 triple helicates.
We report the covalent post-assembly modification of kinetically metastable amine-bearing Fe(II)2L3 triple helicates via acylation and azidation. Covalent modification of the metastable helicates prevented their reorganization to the thermodynamically favored Fe(II)4L4 tetrahedral cages, thus trapping the system at the non-equilibrium helicate structure. This functionalization strategy also conveniently provides access to a higher-order tris(porphyrinatoruthenium)-helicate complex that would be difficult to prepare by de novo ligand synthesis.This work
was supported by the UK Engineering and Physical Sciences
Research Council (EPSRC). D.A.R. acknowledges the Gates
Cambridge Trust for Ph.D. (Gates Cambridge Scholarship) and
conference funding.This is the final published version. It first appeared at http://pubs.acs.org/doi/abs/10.1021/ja5042397
Sequence-controlled methacrylic multiblock copolymers via sulfur-free RAFT emulsion polymerization
Block copolymer synthesis by controlled/living radical polymerisation in heterogeneous systems
Preparation of inert polystyrene latex particles as microRNA delivery vectors by surfactant-free RAFT emulsion polymerization
We present the preparation of 11 nm polyacrylamide-stabilized polystyrene latex particles for conjugation to a microRNA model by surfactant-free RAFT emulsion polymerization. Our synthetic strategy involved the preparation of amphiphilic polyacrylamide-block-polystyrene copolymers, which were able to self-assemble into polymeric micelles and “grow” into polystyrene latex particles. The surface of these sterically stabilized particles was postmodified with a disulfide-bearing linker for the attachment of the microRNA model, which can be released from the latex particles under reducing conditions. These nanoparticles offer the advantage of ease of preparation via a scaleable process, and the versatility of their synthesis makes them adaptable to a range of applications
Fine-needle aspiration for diagnosis of tuberculous lymphadenitis in children in Bangui, Central African Republic
N2 - BACKGROUND: Tuberculosis (TB) is a major cause of childhood morbidity and mortality in developing countries. One of the main difficulties is obtaining adequate specimens for bacteriological confirmation of the disease in children.The aim of this study is to evaluate the adequacy of fine-needle aspiration (FNA) for the diagnosis of TB. METHODS: In a prospective study conducted at the paediatric hospital in Bangui in 2007--2009, we used fine-needle aspiration to obtain samples for diagnosis of TB from 131 children aged 0--17 years with persistent lymphadenitis. RESULTS: Fine-needle aspiration provided samples that could be used for bacteriological confirmation of TB. Ziehl-Neelsen staining for acid-fast bacilli was positive in 42.7% of samples, and culture identified TB in 67.2% of cases. Of 75 samples that were stain-negative, 49 (65.3%) were culture-positive, while 12 stain-positive samples remained culture-negative. Ten of the 12 stain-positive, culture-negative samples were from patients who had received previous antimicrobial therapy. With regard to phenotypic drug susceptibility, 81/88 strains (91.1%) were fully susceptible to isoniazid, rifampicin, ethambutol and streptomycin, six (6.8%) were resistant to one drug, and one multidrug-resistant strain was found. CONCLUSIONS: Fine-needle aspiration is simple, cost-effective and non-invasive and can be performed by trained staff. Combined with rapid molecular diagnostic tests, fine-needle aspirates could improve the diagnosis of TB and provide valuable information for appropriate treatment and drug resistance
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