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Backbone-hydrazone-containing biodegradable copolymeric micelles for anticancer drug delivery

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Abstract

Well-defined biodegradable, pH-sensitive amphiphilic block polymers, poly(ethylene glycol)-Hyd-poly(lactic acid) (mPEG-Hyd-PLA) which have acid-cleavable linkages in their backbones, were synthesized via ring-opening polymerization initiated from hydrazone-containing macroinitiators. Introducing a hydrazone bond onto the backbone of an amphiphilic copolymer will find a broad-spectrum encapsulation of hydrophobic drugs. Dynamic light scattering (DLS) and transmission electron microscopy showed that the diblock copolymers self-assembled into stable micelles with average diameters of 100 nm. The mean diameters and size distribution of the hydrazone-containing micelles changed obviously in mildly acidic pH (multiple peaks from 1 to 202 nm appeared under a pH 4.0 condition) than in neutral, while there were no changes in the case of non-sensitive ones. Doxorubicin (DOX) and paclitaxel (PTX) were loaded with drug loading content ranging from 2.4 to 3.5 %, respectively. Interestingly, the anticancer drugs released from mPEG-Hyd-PLA micelles could also be promoted by the increased acidity. An in vitro cytotoxicity study showed that the DOX-loaded mPEG-Hyd-PLA micelles have significantly enhanced cytotoxicity against HepG2 cells compared with the non-sensitive poly(ethylene glycol)-block-poly(lactic acid) (mPEG-PLA) micelles. Confocal microscopy observation indicated that more DOX were delivered into the nuclei of cells following 6 or 12 h incubation with DOX-loaded mPEG-Hyd-PLA micelles. In vivo studies on H22-bearing Swiss mice demonstrated the superior anticancer activity of DOX-loaded mPEG-Hyd-PLA micelles over free DOX and DOX-loaded mPEG-PLA micelles. These hydrazone-containing pH-responsive degradable micelles provide a useful strategy for antitumor drug delivery.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (NSFC 51375142), Research Fund for Excellent Young College Teachers of Henan Province and a Key Project Funded by the Education Department of Henan Province. Thanks to Professor Gangjun Du for his valuable advice and help in the animal experiments.

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Authors and Affiliations

  1. Institute of Pharmacy, Henan University, North Jinming Rd., Kaifeng, 475004, China

    Jing Xu, Shujuan Luan, Benkai Qin, Yingying Wang, Kai Wang, Peilan Qi & Shiyong Song

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  1. Jing Xu
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  2. Shujuan Luan
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  4. Yingying Wang
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  5. Kai Wang
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  7. Shiyong Song
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Correspondence to Shiyong Song.

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All animal experiments were performed in accordance with the principles of care and use of laboratory animals and were approved by the experimental animal administrative committee of Henan University.

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Jing Xu and Shujuan Luan contributed equally to this work.

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Xu, J., Luan, S., Qin, B. et al. Backbone-hydrazone-containing biodegradable copolymeric micelles for anticancer drug delivery. J Nanopart Res 18, 316 (2016). https://doi.org/10.1007/s11051-016-3626-4

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