基于血管阻断剂和凝血机制的纳米药物肿瘤靶向策略研究

Nanomedicines have enormous potential to reduce the side-effects of chemotherapy drugs and improve the life quality of cancer patients, yet our ability to efficiently home these materials to regions of disease and to improve the efficacy in vivo remains very limited. This also calls for the development of new targeting strategies for cancer therapy. In this proposal, we presented a novel tumor-targeting strategy based on tumor-vascular disrupting agents (VDAs) and clotting process. VDAs like DMXAA and CA4P were applied to selectively induce hemorrhage and blood clotting in cancerous tumor, and then FXIII-substrate peptide decorated on nanmedicines would drive these nano-drugs to accumulate in tumor region. The advantage of this protocol is that there are significantly more artificial targeting sites in tumor regardless the heterogeneity, which may significantly improve the tumor-targeting efficiency with good universality. The tumor-targeting effect, anti-tumor efficacy, and the action mechanism of this strategy will be performed in this study.

将化疗药物与纳米载体相结合制备的纳米抗肿瘤药物在降低药物的毒副作用、提高患者的生存质量方面展示出巨大的应用前景，然而，其在肿瘤部位的靶向输送及疗效提升方面的表现仍难以令人满意。分析原因是目前的基于被动“EPR效应”及肿瘤受体表达特征的药物输送手段难以实现纳米药物在肿瘤部位的高效靶向富集，因此，迫切需要新的靶向输送策略的开发。在本课题中，我们提出一种基于小分子血管阻断剂（VDAs）和体内凝血机制的纳米药物肿瘤靶向新策略：利用VDAs选择性触发瘤内出血发生，通过在纳米药物表面修饰凝血因子FXIII的底物肽对这一凝血过程的参与来实现纳米药物在肿瘤部位的高效靶向富集。这一策略的优势是能够人为在瘤内制造大量的靶向位点，并且不受肿瘤异质性的影响，因此有望大幅提高靶向效率并保持良好的普适性。我们将对该策略下的纳米药物肿瘤富集情况、作用机制、肿瘤治疗效果、以及普适性进行详细考察和阐释。

血管阻断剂是近年来发现的一类靶向肿瘤血管的安全高效的抗肿瘤药物。其通过选择性作用于肿瘤内部新生血管，切断血管下游细胞的氧气和养分供应，造成肿瘤内部的大面积坏死。在本研究项目中，我们提出并发展了三大类基于血管阻断剂的实体肿瘤治疗新策略，包括：1）基于血管阻断剂和凝血机制的纳米药物肿瘤靶向策略；2）联合血管阻断剂和纳米抗肿瘤药物治疗实体肿瘤的策略；3）高分子化血管阻断剂的开发及用于肿瘤治疗的新策略。通过以上课题的实施，实现了纳米抗肿瘤药物在肿瘤内的高度靶向富集，取得了出色的肿瘤治疗效果。本项目的实施发展和完善了血管阻断剂用于实体肿瘤治疗的巨大价值，特别是所提出的高分子化血管阻断剂相较于小分子血管阻断剂显示出显著优势，具备临床开发前景。本项目的实施过程中共发表SCI论文10篇（其中5篇影响因子>7.0）；申请中国发明专利5项（其中1项已授权），培养博士研究生2名，培养硕士研究生2名。

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