A novel tumor targeting drug carrier for optical imaging and therapy.
A novel tumor targeting drug carrier for optical imaging and therapy.
复制标题
用于光学成像和治疗的新型肿瘤靶向药物载体
作者：
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
人血清白蛋白（HSA）是血浆和组织液中天然丰富的蛋白质，具有非凡的配体结合能力，并被提倡作为药物载体以促进药物递送。为了使其具有肿瘤靶向特异性，我们产生了与尿激酶的氨基末端片段（ATF）融合的重组HSA，使融合蛋白与尿激酶受体（uPAR）结合，该受体在许多肿瘤中具有高表达水平，但在正常组织中不表达。为了测试这种双功能蛋白（ATF-HSA）的功效，选择疏水光敏剂（单取代的β-羧基酞菁锌，CPZ）作为细胞毒性剂。开发了稀释-孵育-纯化（DIP）策略以将该CPZ加载到ATF-HSA，形成1：1分子复合物（ATF-HSA：CPZ）。我们证明，CPZ确实嵌入ATF-HSA内的HSA的脂肪酸结合位点1（FA 1），给出了7.5 nm的流体动力学半径，接近HSA的（6.5 nm）。ATF-HSA：CPZ在水溶液中表现出很高的稳定性和显著的光学和物理性质。此外，ATF-HSA：CPZ分子复合物在体外能与重组uPAR结合，并能与肿瘤细胞表面的uPAR结合，对肿瘤细胞具有高效的光动力杀伤作用。在荷瘤小鼠模型中，以0.080 μmol / kg或0.050 mg CPZ / kg小鼠体重的剂量进一步证明了该分子复合物的肿瘤杀伤效力。使用荧光分子断层扫描（FMT），ATF-HSA：CPZ显示在肿瘤中特异性蓄积，重要的是，这种肿瘤保留高于HSA：CPZ。总之，这些结果表明ATF-HSA：CPZ不仅是一种有效的肿瘤特异性细胞毒性剂，而且还是一种有用的肿瘤特异性成像探针。这种双功能蛋白质ATF-HSA也可以用作其他类型的细胞毒性或成像剂的药物载体，使它们对表达uPAR的肿瘤具有特异性。
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.
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