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The Use of Amino Acid Linkers in the Conjugation of Paclitaxel with Hyaluronic Acid as Drug Delivery System: Synthesis, Self-Assembled Property, Drug Release, and In Vitro Efficiency

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Abstract

Purpose

A cell-targeted prodrug with good self-assembly properties in aqueous solution was prepared for the anti-cancer drug paclitaxel, offering great potential for further investigation.

Methods

We synthesized hyaluronic acid (HA) with a specific targeting property as a carrier to conjugate with paclitaxel by inserting different amino acids as spacers, including valine, leucine, and phenylalanine, respectively. The structure of HA-amino acid-paclitaxel conjugates was characterized by 1H NMR and GPC. The loading weight and hydrolysis rate were detected by UV and HPLC, respectively. Their morphology and mean diameter were investigated by SEM and DLS, respectively. The biological activity of HA-amino acid-paclitaxel conjugates was measured by MTT assay and flow cytometry using MCF-7 cells.

Results

The use of amino acids as spacers between drug and carrier facilitated paclitaxel release from the conjugates. Their morphology demonstrated that the prepared prodrugs could self-assemble to form nanoparticles with a narrow size distribution and spherical shape. Furthermore, the prodrugs exhibited increased cytotoxicity as compared to free drug. Flow cytometry analysis showed that MCF-7 cells treated with conjugates were arrested in the G2/M phase of the cell cycle.

Conclusions

Prodrugs synthesized as HA-amino acid-paclitaxel conjugates exhibited enhanced cytotoxicity in breast cancer cell lines and hence may have potential application as tumor-specific nanoparticulate therapeutic agents.

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ACKNOWLEDGEMENT

The authors are grateful for the financial support of 985 Foundation of Ministry of Education. This work was supported by the National Natural Science Foundation of China (Grant No. 20472018), by the Natural Science Foundation of Hunan (Key Project No. 07JJ3019), by the Department of Science and Technology of Changsha (Grant No. K082152).

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Authors and Affiliations

  1. Biomedical Engineering Center, Hunan University, Changsha, Hunan, 410082, People’s Republic of China

    Dingcheng Xin, Ying Wang & Jiannan Xiang

  2. College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan, 410082, People’s Republic of China

    Dingcheng Xin, Ying Wang & Jiannan Xiang

  3. State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, Hunan, 410082, People’s Republic of China

    Ying Wang & Jiannan Xiang

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  1. Dingcheng Xin
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  2. Ying Wang
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Correspondence to Jiannan Xiang.

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Dingcheng Xin and Ying Wang have equal contribution in this work and are both equally considered as first author.

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Xin, D., Wang, Y. & Xiang, J. The Use of Amino Acid Linkers in the Conjugation of Paclitaxel with Hyaluronic Acid as Drug Delivery System: Synthesis, Self-Assembled Property, Drug Release, and In Vitro Efficiency. Pharm Res 27, 380–389 (2010). https://doi.org/10.1007/s11095-009-9997-9

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