Miktoarm polymers are a relatively new and unique class of macromolecules, and constitute a topical area of research due to their intriguing properties which can be tailored by varying their polymer arms. Much emphasis has been placed in the recent past in developing synthetic methodologies to these star polymers, and examining their self-assembly in solution. This review summarizes the progress made in the area of miktoarm star polymers in terms of their synthesis, behavior in solution, and applications. The different synthetic strategies to construct a variety of miktoarm star polymers are described, and each methodology strikes a balance between ease of synthesis and control over the final architecture. The self-assembly of miktoarm polymers in solution is then elaborated, which is frequently studied as a function of either arm-length (an intrinsic property of the star) or the application of an external stimulus (pH, temperature, etc.). This is followed by an overview of the applications of these stars in areas including drug delivery.

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The design and synthesis of a well-defined molecular building block with three orthogonal functionalities which facilitate the construction of ABC-type miktoarm star polymers via a combination of sequential CuI-catalyzed cycloaddition of an azide to an alkyne (“click”) followed by ring-opening polymerization are reported. Using this simple and highly versatile methodology, a variety of miktoarm star polymers were prepared which consisted of hydrophilic poly(ethylene glycol) and hydrophobic polystyrene and poly(ε-caprolactone) arms. Their self-assembly in an aqueous medium was examined using dynamic light scattering and transmission electron microscopy. These ABC miktoarm polymers were found to self-assemble into spherical micelles whose core size and hydrodynamic diameter were found to be inversely proportional to the size of the PEG arm. The potential of encapsulating small molecules into these micelles was explored using Disperse Red 1 dye. An enhancement in the loading capacity of the micelles was observed with an increase in the length of the hydrophobic arm.

a b s t r a c tWe report here the design, synthesis, and properties, of multifunctional niacin nanoconjugates based on dendritic, miktoarm and linear backbone nanocarriers, using "click" chemistry. The conjugates were in this instance used to deliver the therapeutic agent niacin to lipid droplets. The desired combination of niacin, a lipophilic fluorescent dye (BODIPY), and polyethylene glycol (PEG), was achieved by covalently linking the desired agents to the selected carrier. The nanocarriers containing niacin and BODIPY were found almost exclusively within cytoplasmic lipid droplets in the cells used in this study (living hepatocytes and microglia), whereas the trifunctional carrier containing niacin, BODIPY and PEG was partially localized within these organelles but also elsewhere in the cytoplasmic compartment. Spectrofluorometric analyses, confocal microscopy and fluorescence cell sorting revealed different rates and extent of multifunctional conjugate(s) internalization in the two cell types. Even micromolar concentrations of the internalized multifunctional conjugates did not cause significant cell death or mitochondrial functional impairment, suggesting that they are suitable candidate nanostructures for lipid droplet imaging and for targeting drugs to these cellular organelles. These studies provide an efficient and easy way to synthesize multifunctional nanocarriers by click chemistry, applicable to the synthesis of related multifunctional nanostructures and to their use in the targeting of cellular organelles, including lipid droplets.

Conspectus Methods for detecting and quantifying disease biomarkers in biofluids with high specificity and sensitivity play a pivotal role in enabling clinical diagnostics, including point-of-care tests. The most widely used molecular biomarkers include proteins, nucleic acids, hormones, metabolites, and other small molecules. While numerous methods have been developed for analyzing biomarkers, most techniques are challenging to implement for clinical use due to insufficient analytical performance, high cost, and/or other practical shortcomings. For instance, the detection of cell-free nucleic acid (cfNA) biomarkers by digital PCR and next-generation sequencing (NGS) requires time-consuming nucleic acid extraction steps, often introduces enzymatic amplification bias, and can be costly when high specificity is required. While several amplification-free methods for detecting cfNAs have been reported, these techniques generally suffer from low specificity and sensitivity. Meanwhile, the quantification of protein biomarkers is generally performed using immunoassays such as enzyme-linked immunosorbent assay (ELISA); the analytical performance of these methods is often limited by the availability of antibodies with high affinity and specificity as well as the significant nonspecific binding of antibodies to assay surfaces. To address the drawbacks of existing biomarker detection methods and establish a universal diagnostics platform capable of detecting different types of analytes, we have developed an amplification-free approach, named single-molecule recognition through equilibrium Poisson sampling (SiMREPS), for the detection of diverse biomarkers with arbitrarily high specificity and single-molecule sensitivity. SiMREPS utilizes the transient, reversible binding of fluorescent detection probes to immobilized target molecules to generate kinetic fingerprints that are detected by single-molecule fluorescence microscopy. The analysis of these kinetic fingerprints enables nearly perfect discrimination between specific binding to target molecules and any nonspecific binding. Early proof-of-concept studies demonstrated the in vitro detection of miRNAs with a limit of detection (LOD) of approximately 1 fM and >500-fold selectivity for single-nucleotide polymorphisms. The SiMREPS approach was subsequently expanded to the detection of rare mutant DNA alleles from biofluids at mutant allele fractions of as low as 1 in 1 million, corresponding to a specificity of >99.99999%. Recently, SiMREPS was generalized to protein quantification using dynamically binding antibody probes, permitting LODs in the low-femtomolar to attomolar range. Finally, SiMREPS has been demonstrated to be suitable for the in situ detection of miRNAs in cultured cells, the quantification of small-molecule toxins and drugs, and the monitoring of telomerase activity at the single-molecule level. In this Account, we discuss the principles of SiMREPS for the highly specific and sensitive detection of molecular analytes, including considerations for assay desi...

A commercial polychlorinated biphenyl mixture (PCBs), Aroclor 1242, was administered to rats po by intubation in order to determine toxic manifestations of acute and subacute ingestion. In addition, the effect of PCBs on hepatic microsomal enzyme systems in rats was evaluated. The oral, 14day LD50 was determined to be approximately 4.25 g/kg. Major toxic signs observed upon administration of high doses of PCBs included diarrhea, chromodacryorrhea, loss of body weight, unusual stance and gait, lack of response to pain stimuli, and terminal ataxia. Progressive dehydration and CNS depression appeared to be contributing factors in each fatality. Histopathologic alterations were evident only in the liver and kidneys, manifest as foci of sudanophilic vacuolation. Rats maintained on an oral dosage regimen of 100 mg/kg every other day for 3 weeks exhibited similar histopathologic changes, but no overt signs of toxicity. Serum GOT activities were elevated over controls in both the acute and subacute groups. A single ip injection (100 mg/kg) increased liver weight, total hepatic microsomal enzyme activity (measured as hydroxylation of acetanilide and N-demethylation of aminopyrine), and hepatic cytochrome P.,5,, and b5 levels. Hepatic microsomal enzyme activity remained elevated 10 days after a single dose of PCBs, suggesting that PCBs may play an important role in altering biologic responses of mammals subjected to environmental chemical stress. Polychlorinated biphenyls (PCBs) have experienced widespread industrial usage and are now widely distributed throughout the environment (Gustafson, 1970; Peakall and Lincer, 1970). These compounds have been found in the livers of dying pelagic birds (Bourne and Mead, 1969), in fish, mussels, and birds (Koeman et al., 1969), and even in human adipose tissues (Biros et al., 1970). Humans have been inadvertently exposed to PCBs in several instances, including ingestion of PCB-contaminated rice oil in Japan (Kuratsune, 1969), and poultry products in the United States (Pichirallo, 1971). Data on the precise chemical composition and the toxicity of PCBs is at present incomplete. Commercial PCB products are known to consist of mixtures of isomers, differing from one another in the degree of chlorination. Vos and co-workers (1970) reported 2 such products, Clophen and Phenoclor, to be contaminated by trace amounts of chlorinated naphthalenes and highly poisonous chlorinated dibenzofurans. Chlorinated dibenzofurans have been implicated in the toxic action of Clophen and Phenoclor,

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