Alfaleh Mohamed A, Howard Christopher B, Sedliarou Ilya, Jones Martina L, Gudhka Reema, Vanegas Natasha, Weiss Jocelyn, Suurbach Julia H, de Bakker Christopher J, Milne Michael R, Rumballe Bree A, MacDiarmid Jennifer A, Brahmbhatt Himanshu, Mahler Stephen M
Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, Queensland, Australia.
Faculty of Pharmacy; King Abdulaziz University, Jeddah, Saudi Arabia.
PLoS One. 2017 Oct 23;12(10):e0186137. doi: 10.1371/journal.pone.0186137. eCollection 2017.
Human malignant mesothelioma is a chemoresistant tumour that develops from mesothelial cells, commonly associated with asbestos exposure. Malignant mesothelioma incidence rates in European countries are still rising and Australia has one of the highest burdens of malignant mesothelioma on a population basis in the world. Therapy using systemic delivery of free cytotoxic agents is associated with many undesirable side effects due to non-selectivity, and is thus dose-limited which limits its therapeutic potential. Therefore, increasing the selectivity of anti-cancer agents has the potential to dramatically enhance drug efficacy and reduce toxicity. EnGeneIC Dream Vectors (EDV) are antibody-targeted nanocells which can be loaded with cytotoxic drugs and delivered to specific cancer cells via bispecific antibodies (BsAbs) which target the EDV and a cancer cell-specific receptor, simultaneously. BsAbs were designed to target doxorubicin-loaded EDVs to cancer cells via cell surface mesothelin (MSLN). Flow cytometry was used to investigate cell binding and induction of apoptosis, and confocal microscopy to visualize internalization. Mouse xenograft models were used to assess anti-tumour effects in vivo, followed by immunohistochemistry for ex vivo evaluation of proliferation and necrosis. BsAb-targeted, doxorubicin-loaded EDVs were able to bind to and internalize within mesothelioma cells in vitro via MSLN receptors and induce apoptosis. In mice xenografts, the BsAb-targeted, doxorubicin-loaded EDVs suppressed the tumour growth and also decreased cell proliferation. Thus, the use of MSLN-specific antibodies to deliver encapsulated doxorubicin can provide a novel and alternative modality for treatment of mesothelioma.
人类恶性间皮瘤是一种由间皮细胞发展而来的化疗耐药性肿瘤，通常与接触石棉有关。欧洲国家的恶性间皮瘤发病率仍在上升，澳大利亚是世界上按人口计算恶性间皮瘤负担最高的国家之一。使用游离细胞毒性药物进行全身给药的治疗由于缺乏选择性而伴有许多不良副作用，因此存在剂量限制，这限制了其治疗潜力。因此，提高抗癌药物的选择性有可能显著提高药物疗效并降低毒性。EnGeneIC Dream Vectors（EDV）是抗体靶向纳米细胞，可装载细胞毒性药物，并通过双特异性抗体（BsAb）递送至特定癌细胞，该双特异性抗体同时靶向EDV和癌细胞特异性受体。设计BsAb通过细胞表面间皮素（MSLN）将装载阿霉素的EDV靶向癌细胞。使用流式细胞术研究细胞结合和凋亡诱导，并使用共聚焦显微镜观察内化过程。使用小鼠异种移植模型评估体内抗肿瘤作用，随后进行免疫组织化学以进行增殖和坏死的体外评估。BsAb靶向、装载阿霉素的EDV能够在体外通过MSLN受体与间皮瘤细胞结合并内化，并诱导凋亡。在小鼠异种移植模型中，BsAb靶向、装载阿霉素的EDV抑制了肿瘤生长并减少了细胞增殖。因此，使用MSLN特异性抗体递送封装的阿霉素可为间皮瘤治疗提供一种新的替代方法。
