Issue 6, 2013
From the journal:

Biomaterials Science

Enhanced endocytosis of acid-sensitive doxorubicin derivatives with intelligent nanogel for improved security and efficacy†

Jianxun Ding,‡a   Fenghua Shi,‡ab   Di Li,a   Li Chen,*b   Xiuli Zhuang*a  and  Xuesi Chena  

* Corresponding authors

a Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
E-mail: zhuangxl@ciac.jl.cn
Fax: +86 431 85262367
Tel: +86 431 85262367

b Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. China
E-mail: chenl686@nenu.edu.cn
Fax: +86 431 85099667
Tel: +86 431 85099667

Abstract

Three derivatives of doxorubicin (DOX) were prepared by modifying DOX with succinic anhydride, cis-aconitic anhydride and 2,3-dimethylmaleic anhydride, generating acid-insensitive succinyl-DOX (SAD), acid-sensitive cis-aconityl-DOX (CAD) and 2,3-dimethylmaleyl-DOX (DAD) respectively. The pH and reduction dual-responsive methoxy poly(ethylene glycol)-poly(L-lysine-co-L-cystine) nanogel was employed to encapsulate the DOX derivatives. In vitro release studies showed that drug release could be accelerated in the intracellular acidic and reductive conditions. Confocal laser scanning microscopy and flow cytometry results demonstrated that an enhanced intracellular drug release was observed in glutathione monoester pretreated HeLa cells (a human cervical cell line). The DOX derivatives exhibited a lower accumulation in the nuclei than DOX. Moreover, the CAD and DAD-loaded nanogels showed a comparable anti-proliferative activity to the DOX-loaded nanogel against HeLa and HepG2 cells (a human hepatoma cell line). As a comparison, the SAD-loaded nanogel almost never inhibited cellular proliferation. The above results suggested that the pH and reduction dual-responsive nanogel can efficiently deliver acid-sensitive DOX derivatives into the nuclei of cancer cells for minimizing the side effects and enhancing the inhibition of cellular proliferation.

Graphical abstract: Enhanced endocytosis of acid-sensitive doxorubicin derivatives with intelligent nanogel for improved security and efficacy

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Article information

DOI
https://doi.org/10.1039/C3BM60024F
Article type
Paper
Submitted
27 Jan 2013
Accepted
20 Feb 2013
First published
08 Apr 2013

Biomater. Sci., 2013,1, 633-646

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Enhanced endocytosis of acid-sensitive doxorubicin derivatives with intelligent nanogel for improved security and efficacy

J. Ding, F. Shi, D. Li, L. Chen, X. Zhuang and X. Chen, Biomater. Sci., 2013, 1, 633 DOI: 10.1039/C3BM60024F

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