Background
The main challenge of polymeric micelles as drug delivery systems is that the actual delivery efficiency is not as high as expected, which is closely related with the interactions with the complex biological environments such as blood components, phagocytosis, and biodistribution. Herein, we expect to understand these concerns for the clinically relevant micelles that composed of methoxypolyethylene glycol (MPEG) with identical chain length And poly(ε-caprolactone) (PCL) with tunable chain length (PCL
n
-MPEG) (n=20, 30, and 40) wherein doxorubicin was encapsulated as a model drug.
Methods
The doxorubicin-loaded PCL
n
-MPEG micelles were prepared by a dialysis method and characterized by dynamic light scattering and transmission electron microscopy. The surface PEG density and chain conformation were investigated by dissipative particle dynamics simulation. The stability of the micelles was detected by nanoparticle tracking analysis. The effects of PCL chain length on the blood components, phagocytosis, and biodistribution were assayed in vitro and in vivo.
Results
The micelles exhibited spherical morphology with a diameter about 30nm. The PEG chain conformation from “mushroom-like” to “brush-like” was evident. The micelles have no remarkable effect on the red blood cells, blood coagulation, and platelet activation. Interestingly, the protein adsorption was affected and dependent on the chain conformation, with lowest adsorption for PCL
30
-MPEG, which also has the loWest phagocytosis. The stability of the micelles was in the order of PCL
40
-MPEG>PCL
30
-MPEG>PCL
20
-MPEG which was dependent on the PCL chain length. The micelles mainly accumulated in liver, with the order consistent with their stability, indicating that, besides the phagocytosis, the stability of the micelle plays an important role in biodistribution as well. The related mechanisms were proposed and discussed.
Conclusion
Manipulating the PEG/PCL ratio of the micelle is an effective approach to modulate the protein adsorption, phagocytosis, and biodistribution, which may be a prerequisite for clinical applications.
We consider a location-then-price game where two traditional retailers compete with a location-irrelevant online retailer. We characterize the existing equilibria, and we show that in any possible equilibrium there is direct competition between the traditional retailers. Furthermore, the traditional retailers locate at neither a maximal nor minimal distance. In equilibrium, the price of the online retailer might be higher or lower than the price of the traditional retailers, depending on the relative competitiveness of the online retailer and the traditional retailers.
The traditional SOM algorithm need to determine the number of clustering categories in advance, which is very subjective. In this paper, an improved k-means initial value selection algorithm is proposed to calculate the number of clustering categories, which is applied to SOM network model. In this algorithm, the Latent Semantic Indexing is applied in the pre-processing stage of clustering, and the improved SOM algorithm is applied in the text clustering stage. Namely, the number of clustering categories obtained by the improved k-means initial value selection algorithm is taken as the number of neurons in the output layer of SOM network.
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