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Ternary Complexes with Core-Shell Bilayer for Double Level Targeted Gene Delivery: In Vitro and In Vivo Evaluation

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ABSTRACT

Purpose

Hyaluronic acid (HA)/polyethyleneimine-dexamethasone (PEI-Dex)/DNA ternary complexes with “core-shell” bilayer were developed for double level targeted gene delivery. A PEI1800-Dex, as a core, was applied to compact DNA into a nano-sized structure and facilitate the nuclear translocation of DNA after endocytosis into tumor cells, and a polyanion HA, as the outer corona, was employed to improve targeted tumor delivery and reduce cytotoxicity.

Methods

PEI-Dex was synthesized and characterized by 1H NMR. The characterizations of ternary complexes were investigated. Their biological properties, including transfection efficiency, cytotoxicity, cellular uptake and in vivo efficacy were evaluated systemically.

Results

Ternary complexes with the size of about 160 nm exhibited the lowest cytotoxicity and the highest transfection efficiency in B16F10 cells among investigated complexes. The sub-cellular localization study confirmed that ternary complexes could facilitate more efficient cell uptake and nuclear transport of DNA than binary complexes. Moreover, Cy7-labeled ternary complexes obviously accumulated in the tumor after i.v. administration, indicating that ternary complexes could assist the DNA targeting to the tumor. In in vivo studies, HA/PEI1800-Dex/DNA ternary complexes showed confirmed anti-inflammation activity, and could significantly suppress tumor growth of tumor-bearing nude mice.

Conclusions

HA/PEI-Dex/DNA ternary complexes might be a promising targeted gene delivery system.

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ACKNOWLEDGMENTS AND DISCLOSURES

Ying Fan and Jing Yao contributed equally to this work and are both equally considered as first author. This work was supported by the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. JKGQ201107), the National Natural Science Foundation of China (No. 30672548), the fifth of Six Talent Peak Foundation of Jiangsu Province, the Major Project of National Science and Technology of China for New Drugs Development (No.2009ZX09310-004), and the National Basic Research Program of China (No. 2009CB930303).

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Authors and Affiliations

  1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China

    Ying Fan, Jing Yao, Lin Hou, Jianping Zhou, Yun Lu & Qinggang Meng

  2. Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China

    Jing Yao & Jianping Zhou

  3. Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China

    Ronghui Du

  4. Pharmaceutical Sciences Department, Peking University, 38 Xueyuan Road, Haidian District, Beijing, 100191, China

    Qiang Zhang

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  1. Ying Fan
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Correspondence to Jianping Zhou.

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Fan, Y., Yao, J., Du, R. et al. Ternary Complexes with Core-Shell Bilayer for Double Level Targeted Gene Delivery: In Vitro and In Vivo Evaluation. Pharm Res 30, 1215–1227 (2013). https://doi.org/10.1007/s11095-012-0960-9

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  • DOI: https://doi.org/10.1007/s11095-012-0960-9

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