Binding and internalization of NGR-peptide-targeted liposomal doxorubicin (TVT-DOX) in CD13-expressing cells and its antitumor effects
Binding and internalization of NGR-peptide-targeted liposomal doxorubicin (TVT-DOX) in CD13-expressing cells and its antitumor effects
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DOI：
10.1097/cad.0b013e3282a213ce
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发表时间：
2007-11-01
影响因子：
2.3
通讯作者：
Wu, Jinzi J.
中科院分区：
文献类型：
--
作者：
Garde, Seema V.;Forte, Andre J.;Wu, Jinzi J.
为了开发治疗癌症的新药物和分子靶点，人们正在研究天冬氨酸-甘氨酸-精氨酸（NGR）靶向多柔比星（TVT-DOX）脂质体。多柔比星（DOX）脂质体表面的NGR肽靶向肿瘤新生血管特异性的氨基肽酶N （CD13）异构体，使其成为一种有前景的策略。为了进一步了解作用的分子机制，我们在体外研究了TVT-DOX的细胞结合、内化动力学和细胞毒性。我们在体外证明了TVT-DOX与表达cd13的内皮细胞（人脐静脉内皮细胞（HUVEC）和卡波西肉瘤来源的内皮细胞（SLK））和肿瘤（纤维肉瘤，HT-1080）细胞的特异性结合。结合后，药物通过内体途径内化，最终导致阿霉素在细胞核中的定位。TVT-DOX对表达cd13的HUVEC具有选择性毒性，保护cd13阴性的结肠癌细胞HT-29。此外，TVT-DOX的非靶向对应物Caelyx对cd13阳性HUVECs的细胞毒性较低，表明了NGR靶向的体外优势。在人前列腺癌移植裸鼠（PC3）身上检测了TVT-DOX的抗肿瘤活性。在体内观察到PC3肿瘤的显著生长抑制（高达60%）。我们进一步比较了TVT-DOX和游离阿霉素在DOX耐药结肠癌模型HCT-116中的疗效，发现TVT-DOX制剂的抗肿瘤效果比游离DOX更为明显。TVT-DOX在多种血管化实体瘤中的潜在应用前景广阔。
In an effort to develop new agents and molecular targets for the treatment of cancer, aspargine-glycine-arginine (NGR)-targeted liposomal doxorubicin (TVT-DOX) is being studied. The NGR peptide on the surface of liposomal doxorubicin (DOX) targets an aminopeptidase N (CD13) isoform, specific to the tumor neovasculature, making it a promising strategy. To further understand the molecular mechanisms of action, we investigated cell binding, kinetics of internalization as well as cytotoxicity of TVT-DOX in vitro. We demonstrate the specific binding of TVT-DOX to CD13-expressing endothelial [human umbilical vein endothelial cells (HUVEC) and Kaposi sarcoma-derived endothelial cells (SLK)] and tumor (fibrosarcoma, HT-1080) cells in vitro. Following binding, the drug was shown to internalize through, the endosomal pathway, eventually leading to the localization of doxorubicin in cell nuclei. TVT-DOX showed selective toxicity toward CD13-expressing HUVEC, sparing the CD13-negative colon-cancer cells, HT-29. Additionally, the nontargeted counterpart of TVT-DOX, Caelyx, was less cytotoxic to the CD13-positive HUVECs demonstrating the advantages of NGR targeting in vitro. The antitumor activity of TVT-DOX was tested in nude mice bearing human prostate-cancer xenografts (PC3). A significant growth inhibition (up to 60%) of PC3 tumors in vivo was observed. Reduction of tumor vasculature following treatment with TVT-DOX was also apparent We further compared the efficacies of TVT-DOX and free doxorubicin in the DOX-resistant colon-cancer model, HCT-116, and observed the more pronounced antitumor effects of the TVT-DOX formulation over free DOX The potential utility of TVT-DOX in a variety of vascularized solid tumors is promising.