Theranostics 2018; 8(7):2018-2030. doi:10.7150/thno.24382 This issue

Research Paper

A paclitaxel prodrug with bifunctional folate and albumin binding moieties for both passive and active targeted cancer therapy

Lingling Shan1,2, Xin Zhuo1, Fuwu Zhang2, Yunlu Dai2, Guizhi Zhu2, Bryant C. Yung2, Wenpei Fan2, Kefeng Zhai1, Orit Jacobson2, Dale O. Kiesewetter2, Ying Ma2, Guizhen Gao1✉, Xiaoyuan Chen2✉

1. Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou 234000, China
2. Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda 20892, USA

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Shan L, Zhuo X, Zhang F, Dai Y, Zhu G, Yung BC, Fan W, Zhai K, Jacobson O, Kiesewetter DO, Ma Y, Gao G, Chen X. A paclitaxel prodrug with bifunctional folate and albumin binding moieties for both passive and active targeted cancer therapy. Theranostics 2018; 8(7):2018-2030. doi:10.7150/thno.24382. Available from

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Graphic abstract

Folate receptor (FR) has proven to be a valuable target for chemotherapy using folic acid (FA) conjugates. However, FA-conjugated chemotherapeutics still have low therapeutic efficacy accompanied with side effects, resulting from complications such as short circulation half-life, limited tumor delivery, as well as high kidney accumulation. Herein, we present a novel FA-conjugated paclitaxel (PTX) prodrug which was additionally conjugated with an Evans blue (EB) derivative for albumin binding. The resulting bifunctional prodrug prolonged blood circulation, enhanced tumor accumulation, and consequently improved tumor therapeutic efficacy.

Methods: Fmoc-Cys(Trt)-OH was coupled onto PTX at the 7'-OH position for further synthesis of ester prodrug FA-PTX-EB. The targeting ability was investigated using confocal microscopy and flow cytometry. The pharmacokinetics of this bifunctional compound was also studied. Meanwhile, cell viability was evaluated in normal cells and three cancer cell lines by MTT assay. In vivo therapeutic effect was tested on FR-α overexpressing MDA-MB-231 tumor model.

Results: Compared with free PTX, the FA-PTX, PTX-EB and FA-PTX-EB prodrugs increased circulation half-life in mice from 2.19 to 3.82, 4.41, and 7.51 h, respectively. Pharmacokinetics studies showed that the FA-PTX-EB delivered more PTX to tumors than FA-PTX and free PTX. In vitro and in vivo studies demonstrated that FA-EB-conjugated PTX induced potent antitumor activity.

Conclusion: FA-PTX-EB showed prolonged blood circulation, enhanced drug accumulation in tumors, higher therapeutic index, and lower side effects than either free PTX or monofunctional FA-PTX and EB-PTX. The results support the potential of using EB for the development of long-acting therapeutics.

Keywords: Evans blue, circulation half-life, paclitaxel prodrug, tumor therapy.