PDGFRβ-specific affibody-directed delivery of a photosensitizer, IR700, is efficient for vascular-targeted photodynamic therapy of colorectal cancer
PDGFRβ-specific affibody-directed delivery of a photosensitizer, IR700, is efficient for vascular-targeted photodynamic therapy of colorectal cancer
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PDGFR β 特异性亲和体定向递送光敏剂 IR700，可有效用于结直肠癌的血管靶向光动力治疗
DOI：
10.1080/10717544.2017.1407011
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发表时间：
2017-11-28
期刊：
影响因子：
6
通讯作者：
Lu, Xiaofeng
中科院分区：
文献类型：
--
作者：
Shi, Qiuxiao;Tao, Ze;Lu, Xiaofeng
血管靶向光动力学治疗（PDT）是肿瘤治疗的重要策略。传统的血管靶向PDT是通过被动光敏剂（PS）递送实现的，这涉及不良反应的高风险。血管靶向PDT迫切需要主动PS递送。虽然内皮细胞和周细胞是肿瘤血管的主要细胞成分，但很少有人关注周细胞靶向PDT用于癌症治疗。PDGFR β在各种肿瘤的周细胞中大量表达。在该实验中，产生了对PDGFR β具有0.9 nM亲和力的二聚Z（PDGFR β）抗体。Z（PDGFR β）小体显示PDGFR β依赖性周细胞结合。腹腔注射Z（PDGFR β）小体主要分布在周细胞上，因此在LS 174 T肿瘤移植物中积累。Z（PDGFR β）抗体和IR 700染料的缀合物，即Z（IR 700），结合PDGFR β（+）周细胞，但不结合PDGFR β（-）LS 174 T肿瘤细胞。因此，Z（IR 700）介导的PDT在体外诱导周细胞的死亡，但不是LS 174 T肿瘤细胞。在携带LS 174 T肿瘤移植物的小鼠中，Z（IR 700）介导的PDT损伤肿瘤血管，从而通过加强组织缺氧诱导肿瘤破坏。施用Z（IR 700）介导的PDT的肿瘤移植物的平均质量约为对照的20-30%，表明周细胞靶向的PDT对于癌症治疗是有效的。此外，Z（IR 700）介导的PDT增加了肿瘤对照射后注射的TNF相关凋亡诱导配体（TRAIL）的摄取。因此，Z（IR 700）介导的PDT和TRAIL的联合治疗显示出比Z（IR 700）介导的PDT或基于TRAIL的单一疗法更大的肿瘤抑制。这些结果表明，活性血管靶向PDT可以通过使用Z（PDGFR β）抗体定向递送PS来实现。
Vascular-targeted photodynamic therapy (PDT) is an important strategy for cancer therapy. Conventional vascular-targeted PDT has been achieved by passive photosensitizer (PS) delivery, which involves a high risk of adverse effects. Active PS delivery is urgently required for vascular-targeted PDT. Although endothelial cells and pericytes are major cellular components of tumor blood vessels, little attention has been paid to pericyte-targeted PDT for cancer therapy. PDGFR beta is abundantly expressed in the pericytes of various tumors. In this experiment, a dimeric Z(PDGFR beta) affibody with a 0.9 nM affinity for PDGFR beta was produced. The Z(PDGFR beta) affibody showed PDGFR beta-dependent pericyte binding. Intravenously injected Z(PDGFR beta) affibody was predominantly distributed on pericytes and thus accumulated in LS174T tumor grafts. The conjugate of the Z(PDGFR beta) affibody and IR700 dye, i.e. Z(IR700), bound to PDGFR beta(+) pericytes but not to PDGFR beta(-) LS174T tumor cells. Accordingly, Z(IR700)-mediated PDT in vitro induced the death of pericytes but not of LS174T tumor cells. In mice bearing LS174T tumor grafts, Z(IR700)-mediated PDT damaged tumor blood vessels, thus inducing tumor destruction by intensifying tissue hypoxia. The average mass of tumor grafts administered with Z(IR700)-mediated PDT was approximately 20-30% of that of the control, indicating that pericyte-targeted PDT is efficient for cancer therapy. In addition, Z(IR700)-mediated PDT increased the tumor uptake of TNF-related apoptosis-inducing ligand (TRAIL) injected post-illumination. Consequently, combination therapy of Z(IR700)-mediated PDT and TRAIL showed greater tumor suppression than Z(IR700)-mediated PDT- or TRAIL-based monotherapy. These results demonstrated that active vascular-targeted PDT could be achieved by using Z(PDGFR beta) affibody-directed delivery of PS.