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

Research Paper

A Novel Tumor Targeting Drug Carrier for Optical Imaging and Therapy

Rui Li^1,4, Ke Zheng³, Ping Hu¹, Zhuo Chen^1,4, Shanyong Zhou¹, Jincan Chen¹, Cai Yuan¹, Song Chen^1,4, Wei Zheng², En Ma², Fengling Zhang³, Jinping Xue³, Xueyuan Chen^2,4, Mingdong Huang^{1,4 ✉}

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.

✉ Corresponding author: Mingdong Huang, Email address: mhuangac.cn.

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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