Background
Chemodynamic therapy is a promising cancer treatment with specific therapeutic effect at tumor sites, as toxic hydroxyl radical (·OH) could only be generated by Fenton or Fenton-like reaction in the tumor microenvironment (TME) with low pH and high level of endogenous hydrogen peroxide. However, the low concentration of catalytic metal ions, excessive glutathione (GSH) and aggressive hypoxia at tumor site seriously restrict the curative outcomes of conventional chemodynamic therapy.
Results
In this study, polyethylene glycol-phenylboronic acid (PEG-PBA)-modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were synthesized as a targeted nanocarrier to chelate Cu(II) and then encapsulate hypoxia-sensitive drug tirapazamine (TPZ) by the formation of hydrophobic Cu(II)/TPZ complex for hypoxia-enhanced chemo/chemodynamic therapy. The formed G5.NHAc-PEG-PBA@Cu(II)/TPZ (GPPCT) nanoplatform has good stability and hemocompatibility, and could release Cu(II) ions and TPZ quickly in weakly acidic tumor sites via pH-sensitive dissociation of Cu(II)/TPZ. In vitro experiments showed that the GPPCT nanoplatforms can efficiently target murine breast cancer cells (4T1) cells overexpressing sialic acid residues, and show a significantly enhanced inhibitory effect on hypoxic cells by the activation of TPZ. The excessive GSH in tumors could be depleted by the reduction of Cu(II) to Cu(I), and abundant of toxic ·OH would be generated in tumor cells by Fenton reaction for chemodynamic therapy. In vivo experiments demonstrated that the GPPCT nanoplatform could specifically accumulate at tumors, effectively inhibit the growth and metastasis of tumors by the combination of CDT and chemotherapy, and be metabolized with no systemic toxicity.
Conclusions
The targeted GPPCT nanoplatform may represent an effective model for the synergistic inhibition of different tumor types by hypoxia-enhanced chemo/chemodynamic therapy.
Graphical Abstract
The mechanism of honeysuckle quality degeneration in hot air drying was studied by measuring honeysuckle appearance color, relative conductivity, the content of chlorophyll, total phenol and chlorogenic acid. Results showed that enzymatic browning was determined as the major factor in the quality degeneration of hot air dried honeysuckle. Chlorogenic acid as the main substrate of the enzymatic browning decreased obviously in drying. The degradation of chlorophyll was not the main cause of the degeneration of quality and color. The browning level reflected the degree of honeysuckle quality deterioration.
Difference equations arise in many contexts in biological, economic and social sciences., can exhibit a complicated dynamical behavior, from stable equilibria to a bifurcating hierarchy of cycles. There are a lot of fascinating problems, which are often concerned with both mathematical aspects of the fine structure of the trajectories and practical applications. In this paper, we investigate the generalized rational difference equation, a kind of fractional linear maps with two delays. Sufficient conditions for the global asymptotic stability of the zero fixed point are given. For the positive equilibrium, we find the region of parameters in which the positive equilibrium is local asymptotic stable and attracts all positive solutions. As for general solutions, two specific and easy checked conditions on the initial values are obtained to guarantee corresponding solutions to be eventually positive. The upper or lower bound are also provided according to different parameters. Of particular interest for this generalized equation would be the existence of periodic solutions and their stabilities. We get the necessary and sufficient conditions for the existence of period two solutions depending on the combination of delay terms. In addition, the sufficient conditions for the existence of 2 r − and 2d−periodic solutions are obtained too. In the end of the paper, we give examples to illustrate our results.
In recent years, service innovation is a new domain that is being paid more attention by academia. There is very different between service innovation and manufacturing innovation. The form mechanism of service innovation is being analyzed from the perspective of knowledge in the paper, and a co-evolution model that is with aid of organizational learning is set up in order to open out the both relation. Meanwhile, it put forwards new study thinking for research and development of service innovation. At last, it puts forward future direction.
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