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Novel Self-Assembled Micelles With Increased Tumor Penetration and Anti-Tumor Efficiency Against Breast Cancer

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Abstract

Purpose

Recently, docetaxel (DTX) micelles based on retinoic acid derivative surfactants showed lower systemic toxicity and bioequivalence to polysorbate-solubilized docetaxel (Taxotere®) in a phase II clinical study. However, the poor stability of these surfactants in vitro and in vivo led to extremely harsh storage conditions with methanol, and the formed micelles were quickly disintegrated with rapid drug burst release in vivo. To further enhance the stability and accumulation in tumors of DTX micelles, a novel surfactant based on acitretin (ACMeNa) was synthesized and used to prepare DTX micelles to improve anti-tumor efficiency.

Methods

Novel micelle-forming excipients were synthesized, and the micelles were prepared using the thin film hydration technique. The targeting effect in vitro, distribution in the tumor, and its mechanism were observed. Pharmacokinetics and anti-tumor effect were further investigated in rats and tumor-bearing female mice, respectively.

Results

The DTX-micelles prepared with ACMeNa (ACM-DTX) exhibited a small size (21.9 ± 0.3 nm), 39% load efficiency, and excellent stability in vitro and in vivo. Long circulation time, sustained and steady accumulation, and strong penetration in the tumor were observed in vivo, contributing to a better anti-tumor effect and lower adverse effects.

Conclusions

The micelles formed by ACMeNa showed a better balance between anti-tumor and adverse effects. It is a promising system for delivering hydrophobic molecules for cancer therapy.

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Acknowledgements

We thank the staff members of Integrated Laser Microscopy Systerm Nuclear Magnetic Resonance System at the National Facility for Protein Science in Shanghai (NFPS), Zhangjiang Lab, China for providing technical support and assistance in data collection and analysis. We also thank Mr. Zhu Zhou at Pharmacy school of Fudan University for his kindly help in data analysis.

Funding

This work was supported by the Foundation of Shanghai Science and Technology Commission (21DZ2291500), the Original Innovation Fund of Fudan University and Bio-pharmaceutical Research Project of Shanghai Science and Technology Commission (19DZ1910704).

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Authors and Affiliations

  1. National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Shanghai, 201203, People’s Republic of China

    Yani Yang, Yuezhu Zhao, Jie Liu, Chen Ge, Weiwei Zhang, Yue Zhang, Junji Wang, Guohao Sun, Xiujun Lin, Xiaohong Lu, Xiang Tang, Jun He & Weigen Lu

  2. Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, 201203, People’s Republic of China

    Jie Liu & Jing Qin

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  1. Yani Yang
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Correspondence to Jun He, Weigen Lu or Jing Qin.

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Yang, Y., Zhao, Y., Liu, J. et al. Novel Self-Assembled Micelles With Increased Tumor Penetration and Anti-Tumor Efficiency Against Breast Cancer. Pharm Res 39, 2227–2246 (2022). https://doi.org/10.1007/s11095-022-03338-3

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