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Imidazole-Bearing Polymeric Micelles for Enhanced Cellular Uptake, Rapid Endosomal Escape, and On-demand Cargo Release

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Abstract

The complex design of multifunctional nanomedicine is beneficial to overcome the multiple biological barriers of drug delivery, but it also presents additional hurdles to clinical translation (e.g., scaling-up and quality control). To address this dilemma, we employed a simple imidazole-bearing polymer micelle for enhanced cellular uptake, facilitated endosomal escape, and on-demand release of a model drug, SN-38. The micelles were crosslinked by the reversible imidazole/Zn2+ coordination with a drug loading of ca. 4% (w/w) and a diameter less than 200 nm. Under mimicked tumor microenvironment (pH 6.8), the surface charge of micelles reversed from negative to positive, leading to enhanced micelles uptake by model 4T1 cells. Such effect was verified by fluorescent labelling of micelles. Compared to imidazole-free nanocarriers, the charge-reversal micelles delivered significantly more SN-38 to 4T1 cells. Due to the proton sponge effect, imidazole-bearing micelles could rapidly escape from endosomes compared to the control micelles, as evidenced by the kinetic analysis of micelle/endosome co-localization. The coordination crosslinking also enabled the acid-triggered drug release. This work provides a “three birds with one stone” approach to achieve the multifunctionality of nanocarriers without complicated particle design, and opens new avenues of advancing nanomedicine translation via simple tailored nanocarriers.

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Funding

The work was financially supported by the National Natural Science Foundation of China (21650110447), State Key Laboratory of Medicinal Chemical Biology (Nankai University) (2017030), and the innovation fund of Tianjin University (1706).

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Authors and Affiliations

  1. School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, China

    Di Lu, Yang An, Simin Feng, Xiaodan Li, Aiping Fan, Zheng Wang & Yanjun Zhao

  2. State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China

    Zheng Wang

Authors
  1. Di Lu
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  2. Yang An
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  3. Simin Feng
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  4. Xiaodan Li
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  5. Aiping Fan
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  6. Zheng Wang
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  7. Yanjun Zhao
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Corresponding authors

Correspondence to Zheng Wang or Yanjun Zhao.

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Lu, D., An, Y., Feng, S. et al. Imidazole-Bearing Polymeric Micelles for Enhanced Cellular Uptake, Rapid Endosomal Escape, and On-demand Cargo Release. AAPS PharmSciTech 19, 2610–2619 (2018). https://doi.org/10.1208/s12249-018-1092-2

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  • DOI: https://doi.org/10.1208/s12249-018-1092-2

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