Targeting tissue factor on tumour cells and angiogenic vascular endothelial cells by factor VII-targeted verteporfin photodynamic therapy for breast cancer in vitro and in vivo in mice.
Targeting tissue factor on tumour cells and angiogenic vascular endothelial cells by factor VII-targeted verteporfin photodynamic therapy for breast cancer in vitro and in vivo in mice.
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DOI：
10.1186/1471-2407-10-235
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发表时间：
2010-05-26
期刊：
影响因子：
3.8
通讯作者：
Duanmu J
中科院分区：
文献类型：
--
作者：
Hu Z;Rao B;Chen S;Duanmu J
为了克服非靶向光动力疗法(NtPDT)选择性差的缺点，提高非靶向光动力疗法(NtPDT)的治疗效果，本研究旨在通过将因子VII(FVII)蛋白与光敏剂维替普芬偶联，开发一种配体靶向性光动力疗法(TPDT)。FVII是受体组织因子(TF)的天然配体，具有高亲和力和特异性。靶向Tf受体的原因是Tf是血管生成肿瘤血管内皮细胞(VEC)和许多类型的肿瘤细胞(包括实体瘤和白血病)的常见但特异的靶点。将含有突变(Lys341Ala)的小鼠凝血因子VII蛋白(MfVII)通过交联剂EDC与从Visudyne脂质体中提取的Vp共价偶联，再用Sephadex G50自旋柱分离游离Vp。与ntPDT相比，使用mfVII-VP结合物的fVII-tPDT在体外对乳腺癌细胞和血管内皮细胞的杀伤作用以及在小鼠异种移植模型中抑制乳腺肿瘤生长的作用进行了测试。我们发现：(I)fVII蛋白可与VP偶联而不影响其结合活性；(Ii)fVII-tPDT可选择性地杀伤TF表达的乳腺癌细胞和VEGF刺激的血管生成的HUVECs，但对未表达TF的未刺激的HUVEC、CHO-K1和293细胞没有副作用；(Iii)fVII靶向使VP PDT的作用增强三到四倍；(Iii)fVII-tPDT诱导的细胞凋亡和坏死水平明显高于ntPDT；(Iv)fVII-tPDT抑制小鼠乳腺肿瘤生长的作用明显强于ntPDT。我们的结论是，我们在这里报道的以fVII为靶点的VP PDT是一种新的、有效的治疗方法，具有更好的选择性，用于乳腺癌的治疗。由于TF在包括白血病细胞在内的多种肿瘤细胞上表达，并且选择性地表达于血管生成的肿瘤血管内皮细胞上，fVII-tPDT在其他实体肿瘤和白血病的治疗中具有广泛的应用前景。
The objective of this study was to develop a ligand-targeted photodynamic therapy (tPDT) by conjugating factor VII (fVII) protein with photosensitiser verteporfin in order to overcome the poor selectivity and enhance the effect of non-targeted PDT (ntPDT) for cancer. fVII is a natural ligand for receptor tissue factor (TF) with high affinity and specificity. The reason for targeting receptor TF for the development of tPDT is that TF is a common but specific target on angiogenic tumour vascular endothelial cells (VEC) and many types of tumour cells, including solid tumours and leukaemia. Murine factor VII protein (mfVII) containing a mutation (Lys341Ala) was covalently conjugated via a cross linker EDC with Veterporfin (VP) that was extracted from liposomal Visudyne, and then free VP was separated by Sephadex G50 spin columns. fVII-tPDT using mfVII-VP conjugate, compared to ntPDT, was tested in vitro for the killing of breast cancer cells and VEGF-stimulated VEC and in vivo for inhibiting the tumour growth of breast tumours in a mouse xenograft model. We showed that: (i) fVII protein could be conjugated with VP without affecting its binding activity; (ii) fVII-tPDT could selectively kill TF-expressing breast cancer cells and VEGF-stimulated angiogenic HUVECs but had no side effects on non-TF expressing unstimulated HUVEC, CHO-K1 and 293 cells; (iii) fVII targeting enhanced the effect of VP PDT by three to four fold; (iii) fVII-tPDT induced significantly stronger levels of apoptosis and necrosis than ntPDT; and (iv) fVII-tPDT had a significantly stronger effect on inhibiting breast tumour growth in mice than ntPDT. We conclude that the fVII-targeted VP PDT that we report here is a novel and effective therapeutic with improved selectivity for the treatment of breast cancer. Since TF is expressed on many types of cancer cells including leukaemic cells and selectively on angiogenic tumour VECs, fVII-tPDT could have broad therapeutic applications for other solid cancers and leukaemia.
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影响因子：
6.4
作者：
Bhatti, Manpreet;Yahioglu, Gokhan;Deonarain, Mahendra P.
通讯作者：
Deonarain, Mahendra P.
影响因子：
82.9
作者：
Contrino, J;Hair, G;Rickles, FR
通讯作者：
Rickles, FR
影响因子：
7.5
作者：
MULDER, AB;BLOM, NR;BOM, VJJ
通讯作者：
BOM, VJJ
影响因子：
4.2
作者：
Mayo, GL;Melendez, RF;Glickman, RD
通讯作者：
Glickman, RD
影响因子：
46.9
作者：
Birchler, M;Viti, F;Neri, D
通讯作者：
Neri, D