Theranostics 2014; 4(6):642-659. doi:10.7150/thno.8527

Research Paper

A Novel Tumor Targeting Drug Carrier for Optical Imaging and Therapy

Rui Li1,4, Ke Zheng3, Ping Hu1, Zhuo Chen1,4, Shanyong Zhou1, Jincan Chen1, Cai Yuan1, Song Chen1,4, Wei Zheng2, En Ma2, Fengling Zhang3, Jinping Xue3, Xueyuan Chen2,4, Mingdong Huang1,4 ✉

1. State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China;
2. Key Laboratory of Optoelectronic Materials Chemistry and Physics, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China;
3. College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou, Fujian, 350002, China;
4. University of Chinese Academy of Sciences, Beijing, 100049, China.

Abstract

Human serum albumin (HSA), a naturally abundant protein in blood plasma and tissue fluids, has an extraordinary ligand-binding capacity and is advocated as a drug carrier to facilitate drug delivery. To render it tumor targeting specificity, we generated a recombinant HSA fused with the amino-terminal fragment (ATF) of urokinase, allowing the fusion protein to bind to urokinase receptor (uPAR), which is shown to have a high expression level in many tumors, but not in normal tissues. To test the efficacy of this bifunctional protein (ATF-HSA), a hydrophobic photosensitizer (mono-substituted β-carboxy phthalocyanine zinc, CPZ) was chosen as a cytotoxic agent. A dilution-incubation-purification (DIP) strategy was developed to load the ATF-HSA with this CPZ, forming a 1:1 molecular complex (ATF-HSA:CPZ). We demonstrated that CPZ was indeed embedded inside ATF-HSA at the fatty acid binding site 1 (FA1) of HSA, giving a hydrodynamic radius of 7.5 nm, close to HSA's (6.5 nm). ATF-HSA:CPZ showed high stability and remarkable optical and photophysical properties in aqueous solution. In addition, the molecular complex ATF-HSA:CPZ can bind to recombinant uPAR in vitro and uPAR on tumor cell surfaces, and was efficient in photodynamic killing of tumor cells. The tumor-killing potency of this molecular complex was further demonstrated in a tumor-bearing mouse model at a dose of 0.080 μmol / kg, or 0.050 mg CPZ / kg of mouse body weight. Using fluorescent molecular tomography (FMT), ATF-HSA:CPZ was shown to accumulate specifically in tumors, and importantly, such tumor retention was higher than that of HSA:CPZ. Together, these results indicate that ATF-HSA:CPZ is not only an efficient tumor-specific cytotoxic agent, but also an useful tumor-specific imaging probe. This bifunctional protein ATF-HSA can also be used as a drug carrier for other types of cytotoxic or imaging agents to render them specificity for uPAR-expressing tumors.

Keywords: urokinase receptor, amino-terminal fragment of urokinase, human serum albumin, phthalocyanine zinc, tumor targeting, fluorescent molecular tomography.

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How to cite this article:
Li R, Zheng K, Hu P, Chen Z, Zhou S, Chen J, Yuan C, Chen S, Zheng W, Ma E, Zhang F, Xue J, Chen X, Huang M. A Novel Tumor Targeting Drug Carrier for Optical Imaging and Therapy. Theranostics 2014; 4(6):642-659. doi:10.7150/thno.8527. Available from http://www.thno.org/v04p0642.htm