Research Article

5-fluorouracil-caffeic acid cocrystal delivery agent with long-term and synergistic high-performance antitumor effects

School of Medicine & Pharmacy & College of Marine Life Science, Ocean University of China, Qingdao, Shandong, 266003, China

Laboratory for Marine Drugs & Bioproducts, Qingdao National Laboratory for Marine Science & Technology, Shandong, 266003, China

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Fan-Zhi Bu

School of Medicine & Pharmacy & College of Marine Life Science, Ocean University of China, Qingdao, Shandong, 266003, China

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Yu Yu

Qingdao Institute for Food & Drug Control, Qingdao, Shandong, 266071, China

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Cui-Wei Yan

School of Medicine & Pharmacy & College of Marine Life Science, Ocean University of China, Qingdao, Shandong, 266003, China

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Zhi-Yong Wu

School of Medicine & Pharmacy & College of Marine Life Science, Ocean University of China, Qingdao, Shandong, 266003, China

Laboratory for Marine Drugs & Bioproducts, Qingdao National Laboratory for Marine Science & Technology, Shandong, 266003, China

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Yan-Tuan Li

*Author for correspondence: Tel.: +86 8203 2951;

E-mail Address: yantuanli@ouc.edu.cn

https://orcid.org/0000-0002-7475-5591

School of Medicine & Pharmacy & College of Marine Life Science, Ocean University of China, Qingdao, Shandong, 266003, China

Laboratory for Marine Drugs & Bioproducts, Qingdao National Laboratory for Marine Science & Technology, Shandong, 266003, China

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Published Online:17 Mar 2023https://doi.org/10.2217/nnm-2022-0208

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Abstract

Aim: To explore how to transform cocrystals of the anticancer drug 5-fluorouracil (FL) with caffeic acid (CF; FL-CF-2H₂O) into a nanoformulation, a self-assembly strategy of cocrystal-loaded micelles is proposed. Methods: Nanomicelles were assembled to deliver cocrystal FL-CF-2H₂O with synergistic activity, and their in vitro/vivo properties were evaluated by combining theoretical and experimental methods. Result: More cocrystal was packed into the polymers due to the stronger interaction energy during micellar assembly, producing excellent cytotoxicity and pharmacokinetic behavior, especially synergistic abilities and long-term therapy. Conclusion: This case exemplifies the particular benefits of the self-assembly strategy of cocrystal-loaded micelles in keeping a delicate balance between long-term effects and high efficiency for FL, and offers a feasible technical scheme for cocrystal delivery agents for antitumor drugs.

Plain language summary

To exemplify the feasibility of the cocrystal conversion of anticancer drug 5-fluorouracil (FL) with phenolic acid nutrient caffeic acid (CF) into a nanomicelle formulation, and further provide new options for the development of slowed-release cocrystal formulations with long-acting and synergistic antitumor effects, in this study, a cocrystalline complex of FL and CF (cocrystal FL-CF-2H₂O) was loaded into polymer PEG-PCL to successfully assemble the cocrystal nanomicelles by a self-assembly strategy. The morphology of the cocrystal nanomicelles was characterized, and in vitro/vivo properties were evaluated by combining theoretical with experimental methods. The results showed that the cocrystal nanomicelles with regular sphericity and homogeneous particle size had greater drug loading and entrapment efficiency than FL nanomicelles, which is also supported by theoretical predictions of the interaction energy between the cocrystal FL-CF-2H₂O and polymer PEG-PCL. The excellent encapsulation effects give rise to more potent cytotoxicity, better absorption and prolonged retention time in vivo. Relative to FL nanomicelles, the present cocrystal nanomicelles with synergistic antitumor abilities exhibited prominent slowed-release behavior that was more conducive to the long-term maintenance of therapeutic concentrations in vivo. The present case offers a feasible technical scheme for successful nanoformulation research on synergistic antitumor pharmaceutical cocrystals.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

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Vol. 17, No. 30

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History

Received 15 August 2022

Accepted 16 February 2023

Published online 17 March 2023

Published in print December 2022

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Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/nnm-2022-0208

Author contributions

Y-M Yu: data curation, formal analysis, investigation and writing of the original draft. F-Z Bu: visualization, methodology and validation. Y Yu: investigation and validation. C-W Yan: project administration, visualization and resources. Z-Y Wu: visualization, software and funding acquisition. Y-T Li: conceptualization, funding acquisition, supervision and writing: review and editing.

Financial & competing interests disclosure

This project was supported by the Shandong Province Natural Science Foundation (ZR2020MH408, ZR2019MH098). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations.

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