%0 Journal Article
%T 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
%A Zhiwei Hu
%A Benqiang Rao
%A Shimin Chen
%A Jinzhong Duanmu
%J BMC Cancer
%D 2010
%I BioMed Central
%R 10.1186/1471-2407-10-235
%X 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.Accumulating evidence suggests that the receptor tissue factor (TF) is expressed on endothelial cells of pathological blood vessels associated with solid tumours [1-6], wet macular degeneration (wMD) [7,8], and endometriosis[9] but not on endothelial cells of normal blood vessels [1-5,10-13], providing an accessible and specific therapeutic target for these diseases. Because its natural ligand, factor VII (fVII), binds TF with exceptionally high specificity and affinity (up to 10-12 M) [14], we constructed an antibody-like immunoconjugate (Icon) by fusing two fVII peptides to
%U http://www.biomedcentral.com/1471-2407/10/235