Pye Hayley, Butt Mohammed Adil, Funnell Laura, Reinert Halla W, Puccio Ignazio, Rehman Khan Saif U, Saouros Savvas, Marklew Jared S, Stamati Ioanna, Qurashi Maryam, Haidry Rehan, Sehgal Vinay, Oukrif Dahmane, Gandy Michael, Whitaker Hayley C, Rodriguez-Justo Manuel, Novelli Marco, Hamoudi Rifat, Yahioglu Gokhan, Deonarain Mahendra P, Lovat Laurence B
Department for Tissue and Energy, Division of Surgery and Interventional Science, University College London, London, UK.
Upper Gastrointestinal Service, University College London Hospitals NHS Foundation Trust, London, UK.
Oncotarget. 2018 May 1;9(33):22945-22959. doi: 10.18632/oncotarget.25159.
Early oesophageal adenocarcinoma (OA) and pre-neoplastic dysplasia may be treated with endoscopic resection and ablative techniques such as photodynamic therapy (PDT). Though effective, discrete areas of disease may be missed leading to recurrence. PDT further suffers from the side effects of off-target photosensitivity. A tumour specific and light targeted therapeutic agent with optimised pharmacokinetics could be used to destroy residual cancerous cells left behind after resection. A small molecule antibody-photosensitizer conjugate was developed targeting human epidermal growth factor receptor 2 (HER2). This was tested in an mouse model of human OA using a xenograft flank model with clinically relevant low level HER2 expression and heterogeneity. we demonstrate selective binding of the conjugate to tumour versus normal tissue. Light dependent cytotoxicity of the phototherapy agent was observed. In an OA mouse xenograft model the phototherapy agent had desirable pharmacokinetic properties for tumour uptake and blood clearance time. PDT treatment caused tumour growth arrest in all the tumours despite the tumours having a clinically defined low/negative HER2 expression level. This new phototherapy agent shows therapeutic potential for treatment of both HER2 positive and borderline/negative OA.
早期食管腺癌（OA）和癌前发育异常可采用内镜切除和光动力疗法（PDT）等消融技术进行治疗。尽管有效，但可能会遗漏离散的病灶区域，从而导致复发。PDT还存在非靶向光敏性的副作用。一种具有优化药代动力学的肿瘤特异性且光靶向治疗剂可用于破坏切除后残留的癌细胞。开发了一种靶向人表皮生长因子受体2（HER2）的小分子抗体 - 光敏剂偶联物。使用具有临床相关低水平HER2表达和异质性的异种移植侧腹模型，在人OA小鼠模型中对其进行了测试。我们证明了偶联物与肿瘤组织和正常组织的选择性结合。观察到光疗剂的光依赖性细胞毒性。在OA小鼠异种移植模型中，光疗剂具有理想的肿瘤摄取药代动力学特性和血液清除时间。尽管肿瘤具有临床定义的低/阴性HER2表达水平，但PDT治疗使所有肿瘤的生长停滞。这种新型光疗剂显示出治疗HER2阳性和临界/阴性OA的治疗潜力。
