IF7多肽介导隐形纳米粒节拍式化疗逆转肿瘤多药耐药

Multi-drug resistance (MDR) is a major obstacle to the success of cancer chemotherapy. Metronomic chemotherapy aiming at inhibiting tumor angiogenesis with conventional chemotherapeutics is a promising strategy for overcoming MDR. Here, we developed a new nanoparticulate drug delivery system (DDS)- IF7 peptide conjugated, Annexin 1 targeted nanoparticles for paclitaxel (IF7-PTX-NP，IPN), as a model for the investigation of targeted tumor angiogenesis metronomic chemotherapy with respect to reverse MDR. The Preliminary results demonstrate that IPN exerts well tumor angiogenesis targeted and antitumor activity of muti-drug resistence breast cancer.It is mainly through the antiangiogenic effect of PTX, which is specifically delivered into the tumor vascular endothelial cells through the nanoparticle internalization mediated by the interaction of IF7 and over-expressed Annexin 1 receptors on tumor vessels. The present research reveals and highlights the significance of targeted metronomic chemotherapy with nanoparticulate DDS in antiangiogenic cancer therapy. To our knowledge, metronomic chemotherapy is the first time to be used to explore the effect and mechanism of overcoming MDR. Our research provides theory and experimental basis for building new MDR treatment strategy targeted tumor vascular drug delivery systems.

肿瘤多药耐药（Multi-drug resistance，MDR）是抗肿瘤化疗失败的主要原因。节拍式化疗具有肿瘤抗血管生成活性，有望发展成为逆转肿瘤MDR新策略。本项目首次构建IF7多肽修饰，载具有高活性抗血管生成作用的化疗药物紫杉醇（paclitaxel，PTX），主动靶向肿瘤血管内皮细胞Annexin 1受体的新型隐形纳米粒（IF7-PTX-NP，IPN）。以IPN为主动靶向肿瘤血管模型，进行长期、低剂量、间歇期短的节拍式化疗逆转肿瘤MDR的探索性研究。初步研究结果表明，IPN表现出良好的肿瘤血管内皮细胞靶向特性；显著诱导荷MDR人乳腺癌裸鼠肿瘤血管内皮细胞凋亡和肿瘤组织坏死，提示主动靶向肿瘤血管抗血管生成治疗具有抗肿瘤MDR活性。本项目首次探讨采用节拍式化疗靶向肿瘤血管逆转肿瘤MDR的可行性及其机制；为建立肿瘤MDR治疗新策略和发展节拍式化疗新理论提供理论依据和实验基础。

肿瘤多药耐药是临床抗肿瘤治疗失败的关键原因。对纳米粒进行表面修饰的主动靶向肿瘤血管生成的抗肿瘤治疗，赋予抗肿瘤药物肿瘤血管靶向性，治疗靶标指向遗传形状稳定的血管内皮细胞而非易突变的肿瘤细胞，可能会为抗肿瘤治疗提供一种新的治疗策略。本研究设计构建新型药物递送系统-表面IF7多肽修饰，载紫杉醇（PTX）的隐形纳米粒，作为逆转肿瘤多药耐药（multi-drug resistance）抗肿瘤血管生成治疗用载体，评价其逆转肿瘤多药耐药特性及抗肿瘤疗效。探讨IF7-PTX-NP多肽修饰纳米粒通过主动靶向Annexin1靶向肿瘤血管，提高对多药耐药肿瘤的抵抗作用。IF7-PTX-NP粒径大小为156.43 nm, 电位为-15.67 mV，载药量和包封率分别为7.22 %和46.77%。IF7-PTX-NP通过IF7-Anxa1相互作用提高纳米粒内化作用，进而提高HUVEC增殖、迁移和小管形成抑制作用。IF7-PTX-NP通过靶向肿瘤血管，聚集在MCF-7/ADR耐药肿瘤部位，引起肿瘤血管内皮细胞凋亡和肿瘤组织坏死。包载于IF7-PTX-NP的低剂量的紫杉醇（1mg/kg）具有显著 抗肿瘤活性，延迟MCF-7/ADR肿瘤生长。相同的抗肿瘤疗效只有8 mg/kg紫杉醇联合使用耐药P-gp抑制剂XR9576是才能实现。IF7-PTX-NP较强的抗肿瘤疗效通过抗肿瘤血管生成实现，表现在肿瘤微血管密度减少和显著的肿瘤细胞凋亡，同时未观察到明显的毒副反应。该主动靶向肿瘤血管载紫杉醇隐形纳米粒靶向肿瘤血管内皮细胞，为肿瘤多药耐药治疗提供新的治疗策略。