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Transcellular Transport Behavior of the Intact Polymeric Mixed Micelles with Different Polymeric Ratios

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Abstract

In order to better promote the application of the polymeric mixed micelles (PMMs) in oral delivery, in addition to focusing on the improvement of micellar structural stability, it is necessary to obtain the absorption characteristics of the intact micellar particles. In this work, the transport behavior across Caco-2 cells of FS/PMMs composed of Pluronic F127 and Solutol HS15 was tracked by encapsulating an environment-responsive probe into the particles. The specific property of the probe is the water-initiated aggregation-caused quenching (ACQ) ability, by which integral particles can be identified accurately. The influence of polymeric ratios (FS) on the transcellular behavior of FS/PMMs was explored and the single pass intestinal perfusion experiment was used to further illustrate it. Moreover, pharmacokinetics parameters were detected to analyze the relationship among FS ratios, transport behavior, and pharmacokinetic parameters. FS ratios were found to hardly affect the endocytosis pathways and intracellular itinerary of FS/PMMs, but do affect the proportion of each path. FS/PMMs with high HS15 content, namely System-I, were found to primarily undergo receptor-mediated endocytosis pathway and be less susceptible to lysosomal degradation, which would lead to more absorption and higher Cmax and AUC than drug suspension. In contrast, despite System-II with high F127 content cannot contribute to drug plasma concentration, it can prolong the in vivo retention time. These findings provided evidence for the role of polymeric ratios in modulating the transcellular absorption and pharmacokinetic parameters of the drug-loaded PMMs, and would be a step forward in helping PMMs’ design to enhance oral drug delivery.

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Acknowledgements

The authors are thankful to Jiangxi University of Chinese Medicine for the help in conducting this study. Additionally, sincerely thanks to Professor Wu Wei’s team from Fudan University for providing the ACQ probe for this work.

Funding

This work was financially supported by Jiangxi Provincial Natural Science Foundation (20212BAB216013), Jiangxi University of Chinese Medicine Doctoral Research Startup Fund (2021WBZR006), and Science and Technology Innovation Team project (CXTD22006).

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Author notes

  1. Wenting Wu, Quan Ding, and Zhiwei Zhou contributed equally to this work and should be considered co-first authors.

Authors and Affiliations

  1. Institute of Modern Chinese Medicine Pharmaceutical Industry, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China

    Wenting Wu, Lipeng Jiang, Peng Liu, Weiping Ai & Weifeng Zhu

  2. Key Laboratory of Modern Chinese Medicine Preparations Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China

    Quan Ding, Zhiwei Zhou & Wenliang Kuang

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  1. Wenting Wu
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Contributions

Wenting Wu, Weifeng Zhu, and Weiping Ai proposed and designed the project. Wenting Wu wrote the manuscript. Wenting Wu, Quan Ding, and Zhiwei Zhou conducted the experiments. Quan Ding, Zhiwei Zhou, and Wenliang Kuang analyzed the results and generated the figures. Wenliang Kuang, Lipeng Jiang, and Peng Liu assisted with the animal experiments. Wenting Wu, Weifeng Zhu, and Weiping Ai revised and commented on the manuscript. All the authors read and approved the final manuscript.

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Correspondence to Weiping Ai or Weifeng Zhu.

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Wu, W., Ding, Q., Zhou, Z. et al. Transcellular Transport Behavior of the Intact Polymeric Mixed Micelles with Different Polymeric Ratios. AAPS PharmSciTech 24, 69 (2023). https://doi.org/10.1208/s12249-022-02454-y

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