Zhou Xiaolei, Zheng Ke, Li Rui, Chen Zhuo, Yuan Cai, Hu Ping, Chen Jincan, Xue Jinping, Huang Mingdong
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China; University of Chinese Academy of Sciences, Beijing 100049, China.
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China; College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou, Fujian 350002, China.
Acta Biomater. 2015 Sep;23:116-126. doi: 10.1016/j.actbio.2015.05.017. Epub 2015 May 22.
Photodynamic therapy (PDT) has been used as an effective therapeutical modality for tumors. In PDT, a photosensitizer was used to capture the light of specific wavelength, leading to the generation of reactive oxygen species and cytotoxicity surrounding the photosensitizer. Modifications of photosensitizers to enhance tumor specificity are common approaches to increase the efficacy and reduce the side effects of PDT. Previously, we developed a human serum albumin (HSA)-based drug carrier fused with the human amino-terminal fragment (hATF), which binds to a tumor surface marker (urokinase receptor, uPAR). However, hATF-HSA binds to murine uPAR much weaker (79-fold) than to human uPAR, and is not optimal for applications on murine tumor models. In this study, we developed a murine version of the drug carrier (mATF-HSA). A photosensitizer (mono-substituted β-carboxy phthalocyanine zinc, CPZ) was loaded into this carrier, giving a rather stable macromolecule (mATF-HSA:CPZ) that was shown to bind to murine uPAR in vitro. In addition, we evaluated both the photodynamic therapy efficacy and tumor retention capability of the macromolecule (at a dose of 0.05mg CPZ/kg mouse body weight) on murine hepatoma-22 (H22) tumor bearing mouse model. mATF-HSA:CPZ showed more accumulation in tumors compared to its human counterpart (hATF-HSA:CPZ) measured by quantitative fluorescence molecular tomography (FMT). Besides, mATF-HSA:CPZ exhibited a higher tumor killing efficacy than hATF-HSA:CPZ. Together, the macromolecule mATF-HSA is a promising tumor-specific drug carrier on murine tumor models and is an useful tool to study tumor biology on murine tumor models.
光动力疗法（PDT）已被用作治疗肿瘤的一种有效方法。在光动力疗法中，一种光敏剂被用于捕获特定波长的光，从而导致在光敏剂周围产生活性氧物质和细胞毒性。对光敏剂进行修饰以增强肿瘤特异性是提高光动力疗法疗效和降低其副作用的常用方法。此前，我们开发了一种与人氨基末端片段（hATF）融合的基于人血清白蛋白（HSA）的药物载体，该片段可与肿瘤表面标志物（尿激酶受体，uPAR）结合。然而，hATF-HSA与鼠uPAR的结合力比与人uPAR的结合力弱得多（79倍），因此不适用于鼠肿瘤模型。在本研究中，我们开发了一种鼠源版本的药物载体（mATF-HSA）。将一种光敏剂（单取代β-羧基酞菁锌，CPZ）装载到该载体中，得到一种相当稳定的大分子（mATF-HSA:CPZ），体外实验表明其可与鼠uPAR结合。此外，我们在荷鼠肝癌-22（H22）肿瘤小鼠模型上评估了该大分子（剂量为0.05mg CPZ/kg小鼠体重）的光动力治疗效果和肿瘤滞留能力。通过定量荧光分子断层扫描（FMT）测量发现，与相应的人源大分子（hATF-HSA:CPZ）相比，mATF-HSA:CPZ在肿瘤中的蓄积更多。此外，mATF-HSA:CPZ表现出比hATF-HSA:CPZ更高的肿瘤杀伤效果。总之，大分子mATF-HSA是一种在鼠肿瘤模型上很有前景的肿瘤特异性药物载体，也是研究鼠肿瘤模型肿瘤生物学的有用工具。
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