A new type of block copolymer micelles for pH-triggered delivery of poorly water-soluble anticancer drugs has been synthesized and characterized. The micelles were formed by the self-assembly of an amphiphilic diblock copolymer consisting of a hydrophilic poly(ethylene glycol) (PEG) block and a hydrophobic polymethacrylate block (PEYM) bearing acid-labile ortho ester side-chains. The diblock copolymer was synthesized by atom transfer radical polymerization (ATRP) from a PEG macro-initiator to obtain well-defined polymer chain-length. The PEG-b-PEYM micelles assumed a stable core-shell structure in aqueous buffer at physiological pH with a low critical micelle concentration as determined by proton NMR and pyrene fluorescence spectroscopy. The hydrolysis of the ortho ester side-chain at physiological pH was minimal yet much accelerated at mildly acidic pHs. Doxorubicin (Dox) was successfully loaded into the micelles at pH 7.4 and was released at much higher rate in response to slight acidification to pH 5. Interestingly, the release of Dox at pH 5 followed apparently a biphasic profile, consisting of an initial fast phase of several hours followed by a sustained release period of several days. Dox loaded in the micelles was rapidly taken up by human glioma (T98G) cells in vitro, accumulating in the endolysosome and subsequently in the nucleus in a few hours, in contrast to the very low uptake of free drug at the same dose. The dose-dependent cytotoxicity of the Dox-loaded micelles was determined by the MTT assay and compared with that of the free Dox. While the empty micelles themselves were not toxic, the IC50 values of the Dox-loaded micelles were approximately ten-times (by 24 hours) and three-times (by 48 hours) lower than the free drug. The much enhanced potency in killing the multi-drug-resistant human glioma cells by Dox loaded in the micelles could be attributed to high intracellular drug concentration and the subsequent pH-triggered drug release. These results establish the PEG-b-PEYM block copolymer with acid-labile ortho ester side-chains as a novel and effective pH-responsive nano-carrier for enhancing the delivery of drugs to cancer cells.

Kullback–Leibler information, Fisher information, mutual information, multidimensional computerized adaptive test, continuous entropy,

Cognitive diagnostic computerized adaptive testing (CD-CAT) purports to combine the strengths of both CAT and cognitive diagnosis. Cognitive diagnosis models aim at classifying examinees into the correct mastery profile group so as to pinpoint the strengths and weakness of each examinee whereas CAT algorithms choose items to determine those strengths and weakness as efficiently as possible. Most of the existing CD-CAT item selection algorithms are evaluated when test length is relatively long whereas several applications of CD-CAT, such as in interim assessment, require an item selection algorithm that is able to accurately recover examinees' mastery profile with short test length. In this article, we introduce the mutual information item selection method in the context of CD-CAT and then provide a computationally easier formula to make the method more amenable in real time. Mutual information is then evaluated against common item selection methods, such as Kullback-Leibler information, posterior weighted Kullback-Leibler information, and Shannon entropy. Based on our simulations, mutual information consistently results in nearly the highest attribute and pattern recovery rate in more than half of the conditions. We conclude by discussing how the number of attributes, Q-matrix structure, correlations among the attributes, and item quality affect estimation accuracy.

There has recently been much interest in computerized adaptive testing (CAT) for cognitive diagnosis. While there exist various item selection criteria and different asymptotically optimal designs, these are mostly constructed based on the asymptotic theory assuming the test length goes to infinity. In practice, with limited test lengths, the desired asymptotic optimality may not always apply, and there are few studies in the literature concerning the optimal design of finite items. Related questions, such as how many items we need in order to be able to identify the attribute pattern of an examinee and what types of initial items provide the optimal classification results, are still open. This paper aims to answer these questions by providing non-asymptotic theory of the optimal selection of initial items in cognitive diagnostic CAT. In particular, for the optimal design, we provide necessary and sufficient conditions for the Q-matrix structure of the initial items. The theoretical development is suitable for a general family of cognitive diagnostic models. The results not only provide a guideline for the design of optimal item selection procedures, but also may be applied to guide item bank construction.

1. The pharmacokinetics study of Paeoniflorin (Pae) and its acylated derivative (CP-25) was performed. 2. The structure of CP-25 was identified by mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR). The rats were injected with CP-25(6, 12, 24 mg/kg) and orally treated with CP-25 (32, 64, 128 mg/kg), respectively. An high-performance liquid chromatography (HPLC) assay was developed to determine the plasma concentrations of Pae and CP-25. 3. The results of MS and NMR showed that the acylated product was Pae-6'O-benzene sulfonate (CP-25). The plasma levels in oral CP-25 groups were detectable, whereas those of Pae in the oral groups (25 and 50 mg/kg) were undetectable. More specifically, the C values of oral CP-25 were 0.12, 0.19 and 0.44 μg/ml, and the corresponding t of CP-25 were 1.44, 2.12 and 2.11 h, respectively. In addition, the t values of intravenous CP-25 were 161.99, 152.81 and 153.76 min, respectively. 4. Compared with the venous pharmacokinetics parameters of Pae, those of the t, MRT, Vd and CL/F in the CP-25 groups increased noticeably. As expected, compared with oral parameters of Pae, those of t, t, AUC, MRT and Vd in the CP-25 group increased obviously. Finally, the absolute bioavailability of Pae and CP-25 were 3.6 and 10.6%, respectively. 5. Our results indicate that CP-25 is characterized by improved absorption, well distribution, lower clearance, long mean residence time, and moderate bioavailability in rats.

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In this work, we synthesize dodecyl mercaptan-functionalized silver nanoparticles integrated with polypropylene nanocomposite (DM-AgNPs/PP) substrates by a simple in situ melt blending method. The formation and distribution of AgNPs are confirmed by UV–visible spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy, and thermogravimetric analysis. The existence of DM-AgNPs in PP film substrate enhances the thermal degradation and crystallization properties. Further, the antimicrobial activity of as-synthesized DM-AgNPs/PP film substrate is studied using Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria as model microbes, which displayed significantly enhanced bacteriostatic activities under optimized composition and experimental conditions. Interestingly, PP substrate with 0.4% DM-AgNPs exhibits drastically improved antibacterial property via the release of oxygen reactive species and Ag ion diffusion processes; thus, the inhibition rates of E. coli and S. aureus are obtained as 100 and 84.6%, respectively, which is higher than the conventional AgNPs. Finally, we demonstrate the migration study of Ag ions from the DM-AgNPs/PP film using different food simulant solutions by inductively coupled plasma–mass spectrometry analysis and the dissolved Ag ion content is estimated, which is a key prospect for the toxicity analysis. The overall Ag ion migration value is estimated between 1.8 and 24.5 μg/cm2 and displayed a lowest limit of Ag ion migration as 0.36 μg/cm2. Our work highlights the development of high performance nanocomposites as promising antibacterial and food simulant materials for biomedical and industrial applications.

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