Tumor angiogenesis therapy using targeted delivery of Paclitaxel to the vasculature of breast cancer metastases.
Tumor angiogenesis therapy using targeted delivery of Paclitaxel to the vasculature of breast cancer metastases.
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DOI：
10.1155/2014/865732
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发表时间：
2014
影响因子：
--
通讯作者：
Shoji M
中科院分区：
文献类型：
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作者：
Zhu S;Kisiel W;Lu YJ;Petersen LC;Ndungu JM;Moore TW;Parker ET;Sun A;Liotta DC;El-Rayes BF;Brat DJ;Snyder JP;Shoji M
乳腺癌组织和癌血管内皮细胞异常表达组织因子（TF）。TF在癌症血管生成、生长和转移中起核心作用，因此是治疗和药物递送的靶标。TF是因子VIIa（fVIIa）的同源受体。我们将PTX（紫杉醇，也称为Taxol）与三肽苯丙氨酸-苯丙氨酸-精氨酸氯甲基酮（FFRck）偶联，并将其与fVIIa缀合。这项工作的主要目的是评估PTX-FFRck-fVIIa对PTX耐药乳腺癌细胞系的抗血管生成作用。将混合有VEGF和MDA-231的Matrigel皮下注射到无胸腺裸鼠的侧腹。通过尾静脉注射PTX-FFRck-fVIIa缀合物、未缀合的PTX或PBS处理动物。与PBS和未缀合的PTX相比，PTX-FFRck-fVIIa缀合物显著降低基质胶中的微血管密度（p < 0.01-0.05）。通过静脉注射表达荧光素酶的MDA-231细胞建立裸鼠乳腺癌肺转移模型。用PTX-FFRck-fVIIa缀合物或PBS类似地静脉内处理动物。与对照相比，缀合物显著抑制肺转移，突出了其拮抗转移性癌中血管生成的潜力。总之，PTX缀合至fVIIa是用于改善选择性药物递送和抑制血管生成的有前景的治疗方法。
Breast cancer aberrantly expresses tissue factor (TF) in cancer tissues and cancer vascular endothelial cells (VECs). TF plays a central role in cancer angiogenesis, growth, and metastasis and, as such, is a target for therapy and drug delivery. TF is the cognate receptor of factor VIIa (fVIIa). We have coupled PTX (paclitaxel, also named Taxol) with a tripeptide, phenylalanine-phenylalanine-arginine chloromethyl ketone (FFRck) and conjugated it with fVIIa. The key aim of the work is to evaluate the antiangiogenic effects of PTX-FFRck-fVIIa against a PTX-resistant breast cancer cell line. Matrigel mixed with VEGF and MDA-231 was injected subcutaneously into the flank of athymic nude mice. Animals were treated by tail vein injection of the PTX-FFRck-fVIIa conjugate, unconjugated PTX, or PBS. The PTX-FFRck-fVIIa conjugate significantly reduces microvessel density in matrigel (p < 0.01–0.05) compared to PBS and unconjugated PTX. The breast cancer lung metastasis model in athymic nude mice was developed by intravenous injection of MDA-231 cells expressing luciferase. Animals were similarly treated intravenously with the PTX-FFRck-fVIIa conjugate or PBS. The conjugate significantly inhibits lung metastasis as compared to the control, highlighting its potential to antagonize angiogenesis in metastatic carcinoma. In conclusion, PTX conjugated to fVIIa is a promising therapeutic approach for improving selective drug delivery and inhibiting angiogenesis.