Targeted tumor cell internalization and imaging of multifunctional quantum dot-conjugated immunoliposomes in vitro and in vivo
Targeted tumor cell internalization and imaging of multifunctional quantum dot-conjugated immunoliposomes in vitro and in vivo
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DOI：
10.1021/nl801488u
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发表时间：
2008-09-01
期刊：
影响因子：
10.8
通讯作者：
Park, John W.
中科院分区：
文献类型：
--
作者：
Weng, Kevin C.;Noble, Charles O.;Park, John W.
靶向给药系统将成像和治疗方式结合在一个单一的大分子结构中，可能在纳米药物的开发和应用方面提供优势。为了将发光量子点(QD)独特的光学性质结合到免疫脂质体中用于癌症诊断和治疗，我们介绍了QD-ILS的合成、生物物理特性、肿瘤细胞选择性内化和抗癌药物输送。同时考察了QD-ILS的药代动力学特性和体内显影能力。冷冻断裂电子显微镜用于观察裸露的量子点、脂质体对照组、非靶向QD-LS和QD-ILS。流式细胞仪和共聚焦显微镜分析显示，通过插入抗HER2单链抗体制备的QD-ILS在HER2高表达的SK-BR-3和MCF-7/HER2细胞中具有有效的受体介导的内吞作用，而在对照MCF-7细胞中不能。相反，非靶向QD-L在这些细胞中显示出最小的结合和摄取。载阿霉素的QD-ILS显示出有效的抗癌活性，而没有化疗有效载荷的QD-ILS没有观察到细胞毒性。在裸鼠中，QD-ILS显著延长了量子点的循环，与t(1/2)和lt；10min的游离量子点相比，其血浆末端半衰期(t(1/2))接近2.9h。在MCF-7/HER2异种移植模型中，体内荧光成像证实了QD-ILS在肿瘤部位的定位。
Targeted drug delivery systems that combine imaging and therapeutic modalities in a single macromolecular construct may offer advantages in the development and application of nanomedicines. To incorporate the unique optical properties of luminescent quantum dots (QDs) into immunoliposomes for cancer diagnosis and treatment, we describe the synthesis, biophysical characterization, tumor cell-selective internalization, and anticancer drug delivery of QD-conjugated immunoliposome-based nanoparticles (QD-ILs). Pharmacokinetic properties and in vivo imaging capability of QD-ILs were also investigated. Freeze-fracture electron microscopy was used to visualize naked QDs, liposome controls, nontargeted QD-conjugated liposomes (QD-Ls), and QD-ILs. QD-ILs prepared by insertion of anti-HER2 scFv exhibited efficient receptor-mediated endocytosis in HER2-overexpressing SK-BR-3 and MCF-7/HER2 cells but not in control MCF-7 cells as analyzed by flow cytometry and confocal microscopy. In contrast, nontargeted QD-Ls showed minimal binding and uptake in these cells. Doxorubicin-loaded QD-ILs showed efficient anticancer activity, while no cytotoxicity was observed for QD-ILs without chemotherapeutic payload. In athymic mice, QD-ILs significantly prolonged circulation of QDs, exhibiting a plasma terminal half-life (t(1/2)) of similar to 2.9 h as compared to free QDs with t(1/2) < 10 min. In MCF-7/HER2 xenograft models, localization of QD-ILs at tumor sites was confirmed by in vivo fluorescence imaging.