Construction of drug penetration dynamic model based on three-dimensional cell model and application of drug penetration dynamic model to drug evaluation

Abstract

The invention creatively discloses a drug penetration dynamic evaluation method based on a three-dimensional cell model. The method comprises the steps that (1) a three-dimensional somatic cell model and a "penetration dynamics" mathematic model are established, the penetration behavior of an antitumor drug in somatic cells and an accumulation process in all layers of cells are described semi-quantitatively, and fitting is performed to obtain corresponding dynamic parameters; (2) drug concentrations in all layers of cells at different time points after the drug is given according to different concentrations can be subjected to backward prediction based on the obtained dynamic parameters, and the prediction result is highly consistent with an experience result; (3) biological factors influencing characteristic dynamic parameters are analyzed, the penetration behavior of the drug in tumor tissue is speculated according to a plasma drug concentration time course, and the speculation result is highly consistent with an experiment result; and (4) the model and the evaluation method are applied to a second-phase clinical drug INNO-206, and reasons for superiority of the clinical effect of the drug to that of doxorubicin are expounded from the aspect of in-tumor penetration, so that the universality of the method is further verified.

Description

technical field [0001] The present invention relates to multiple fields such as pharmacokinetics, pharmacology, statistics, and mathematical modeling methods, and innovatively establishes a method for evaluating drug penetration kinetics based on a three-dimensional cell model, which can semi-quantitatively describe antitumor drugs Penetration and accumulation kinetics in solid tumors, realize the prediction of in vivo experimental results based on in vitro experimental results, and apply it to the small molecule antitumor drug doxorubicin and the albumin-bound macromolecular prodrug INNO- 206, providing a reasonable and reliable new method for the evaluation of anti-tumor drug penetration in tumors and the development of anti-tumor drugs. Background technique [0002] With the intensification of clinical needs and the rapid development of tumor biology research, a large number of anti-tumor candidate compounds and nano-preparations based on new mechanisms of action and targ...

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Problems solved by technology

However, this evaluation method is always at the stage of describing the phenomenon, and there are many limitations: (1) It cannot accurately characterize the in vivo experimental results: You J et al. found that the penetration and accumulation of magnetic nanoparticles in spheroid cells are However, the in vivo results show the opposite trend. The reason for this phenomenon is that the drug exposure in the in vitro spheroid cell experiment is always in a constant and excessive state, thus ignoring its role in the blood circulation in vivo. Metabolic disposal process, and this problem is also an important factor that causes the in vitro experiment and in vivo experiment to be irrelevant; (2) The repeatability and universality of the existing evaluation methods are poor: the small molecule drug doxorubicin is tested in a sphere with a diameter of 250 μm The penetrating ability in cells varies with different cell lines. After 8 hours of doxorubicin administration in 250SH-SY5Y-MCTS, doxorubicin can penetrate to 50% of the periphery, while for BCG-823- As far as MCTS is concerned, it only penetrates to 10% of the periphery. The results suggest that the penetration ability of the same drug in spheroid models cultured by different cell lines is different. In the process of transforming from a spheroid cell model to an in vivo tumor model, the total distance that the drug needs to penetrate and the physical and chemical properties of the tumor itself are two extremely important changing parameters. If the drug penetration ability cannot be clarified Directly influencing factors, quantitative evaluation of the relationship between various factors and penetration ability, the applicability and universality of drug penetration kinetics evaluation will be greatly limited, and the accuracy of its in vitro-in vivo transformation will be reduced

However, since the application of mathematical models in drug penetration kinetics is still in the ascendant stage, the existing models are not well integrated in the description of pharmacokinetic behavior. The complete process of tumor tissue exposure, drug penetration between tumor tissues, drug uptake by tumor cells in different regions, and elimination of anti-tumor drugs from tissues, therefore, the existing models are not yet accurate from in vitro experiments. Results Prediction and analysis of distribution in tumors in vivo

As mentioned above, the intratumoral penetration of anticancer drugs is a complex process with many influencing factors. Simple use of a model to complete the description may cause problems such as too many parameters, complicated calculations, and uncertainty of multiple variables.

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