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Heparin–Paclitaxel Conjugates Using Mixed Anhydride as Intermediate: Synthesis, Influence of Polymer Structure on Drug Release, Anticoagulant Activity and In Vitro Efficiency

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Abstract

Purpose

The heparin–paclitaxel conjugates using amino acid as linker (HD2), with low anticoagulant activity, the similar anticancer activity as paclitaxel, offer great potential for further investigation.

Methods

Two types of heparin–paclitaxel conjugates (HD) have been developed, in which O-acetylated heparin as carrier conjugates with paclitaxel by direct ester bond (HD1) and by inserting different amino acids as spacers, including valine, leucine, and phenylalanine (HD2a, HD2b, and HD2c), respectively. Specifically, mixed anhydride groups of carrier as activating intermediates mediate the synthesis of prodrugs. The HD conjugates are characterized by 1H NMR, FT-IR and GPC. The percentage weight of drug and hydrolysis rate for HD are detected by UV and HPLC. The anticoagulant activity and cell cycle of MCF-7 of HD are measured by APTT and FCM, respectively.

Results

HD2 conjugates show better solubility and faster hydrolysis rates than those of HD1. Meanwhile, the anticoagulant activity of HD is reduced and FCM analysis show that MCF-7 cells treated with HD are arrested in the G2/M phase of cell cycle.

Conclusions

Amino acids as linkers between paclitaxel and carrier are appropriate to facilitate the release of paclitaxel from carrier. Mixed anhydrides mediate the synthesis of prodrugs and HD2 conjugates are expected to further investigate in vivo experiment.

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ACKNOWLEDGEMENT

We thank Dr. Chunyi Tong from the Institute of Life Science and Biotechnology in Hunan University for his assistance with the experimental procedures during biomedical assays. The authors are grateful for the financial support of 985 Project 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) and Doctoral Fund of Ministry of Education of China (grant no. 20060532022) and Department of Science and Technology Foundation of Changsha (grant no. K0802152-31).

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Authors and Affiliations

  1. Biomedical Engineering Center, Hunan University, Changsha, 410082, China

    Ying Wang, Dingcheng Xin, Kaijian Liu & Jiannan Xiang

  2. College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China

    Ying Wang, Dingcheng Xin, Kaijian Liu & Jiannan Xiang

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

    Ying Wang & Jiannan Xiang

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

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Wang, Y., Xin, D., Liu, K. et al. Heparin–Paclitaxel Conjugates Using Mixed Anhydride as Intermediate: Synthesis, Influence of Polymer Structure on Drug Release, Anticoagulant Activity and In Vitro Efficiency. Pharm Res 26, 785–793 (2009). https://doi.org/10.1007/s11095-008-9762-5

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  • DOI: https://doi.org/10.1007/s11095-008-9762-5

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